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Cerebellar network plasticity: From genes to fast oscillation
Abstract
The role of the cerebellum has been increasingly recognized not only in motor control but in sensory, cognitive and emotional learning and regulation. Purkinje cells, being the sole output from the cerebellar cortex, occupy an integrative position in this network. Plasticity at this level is known to critically involve calcium signaling. In the last few years, electrophysiological study of genetically engineered mice has demonstrated the topical role of several genes encoding calcium-binding proteins (calretinin, calbindin, parvalbumin). Specific inactivation of these genes results in the emergence of a fast network oscillation (ca. 160 Hz) throughout the cerebellar cortex in alert animals, associated with ataxia. This oscillation is produced by synchronization of Purkinje cells along the parallel fiber beam. It behaves as an electrophysiological arrest rhythm, being blocked by sensorimotor stimulation. Pharmacological manipulations showed that the oscillation is blocked by GABA(A) and NMDA antagonists as well as gap junction blockers. This cerebellar network oscillation has also been documented in mouse models of human conditions with complex developmental cerebellar dysfunction, such as Angelman syndrome and fetal alcohol syndrome. Recent evidence suggests a relationship between fast oscillation and cerebellar long term depression (LTD). This may have major implications for future therapeutic targeting.
... Synchronization is an activity pattern commonly observed in the cerebellar cortex, but its prominence between neighboring units underlines the importance of studying the cerebellar local networks. More elaborated forms of patterned activity have also been observed in the cerebellar cortex, with notably a number of normal and pathological rhythmic activities (reviews in Cheron et al., 2008;De Zeeuw et al., 2008). Multi-electrodes studies (e.g. ...
... The Purkinje cells receive more excitation information from precerebellar nuclei and inferior olive, the network noise decreased the possibility of observation this organization in local field potential, without shifting the frequency bands. This may be a reason why the HFO was also not observed in wildtype mouse (Cheron et al., 2008). In our cases, when rats were during active exploration, the chance to observe the HFO in LFP decreased and the peak amplitude of HFO is significant smaller than during sleep. ...
... Journal of Neuroscience 24, 434-441. Cheron, G.,Servais, L., Dan, B., 2008. Cerebellar network plasticity: from genes to fast oscillation. ...
The cerebellum is a brain structure involved in coordination complex motor actions such as voluntary movements. To achieve this function, the precise temporal control of a large population of neurons is required. While a large number of patterned population activity has been characterized in many major brain structures (thalamo-cortical system, basal ganglia, hippocampal formation, etc...), very little is currently known in the cerebellum. Therefore, I investigated the presence and characteristics of such an organization in freely-moving rats, especially when they perform a reach-and-grasp task. The cerebellar cortex has a strong topographical organization, such that neighboring cells share similar input sources and output targets. Therefore, studying the local network properties in the cerebellar cortex allows to access to functionally-relevant population activity. First, I demonstrated that multi-wire electrodes, tetrodes, may be used to record multiple neighboring cells in chronic recordings of freely behaving animals using a custom-made microdrive. Second, I examined in the area of the cerebellar cortex controlling limb movements how the principle cells (the Purkinje cells) coordinate their firing during rest and fast forelimb motor action. Using simultaneous electrophysiological recordings of multiple single cells, I found that neighboring Purkinje cells exhibit consistently a co-modulation of their firing rate at time scale of a few milliseconds. This correlated firing is observed during sleep and active exploration, and increases during motor execution. Our results thus indicate that during a fast and complex movement, local assemblies of Purkinje cells form dynamically at short time scales and will produce very transient episodes of inhibition in the deep cerebellar nuclei. Third, in a collaboration with the group of Richard Courtemanche, we studied the link between neuronal firing and slow local field oscillations that are observed in the cerebellum at rest. We found that a large proportion of Golgi cells and Purkinje cells are modulated during the oscillations. These results indicate that these slow oscillations, that may be also observed in the motor cortex, are propagated in the cerebellar cortex. Overall, my work has identified and characterized a number of state-dependent population activity patterns in the cerebellar cortex. How these patterns impact on the motor system largely remains to be understood and should be examined in future studies.
... At the time, these oscillations were demonstrated to specifically originate from the cerebellar cortex (Dow, 1938 ). In a more recent series of studies, using microelectrodes to record from within cerebellar cortex of mutant mice, this type of fast activity (>150 Hz) was recorded by Cheron et al. (2008). In a mouse model of Angelman syndrome, they found prominent fast oscillations while recording LFPs, along with single unit activity (Cheron et al., 2004Cheron et al., , 2008 Gall et al., 2005), and confirmed with precision the link of these oscillations with PC activity. ...
... In a more recent series of studies, using microelectrodes to record from within cerebellar cortex of mutant mice, this type of fast activity (>150 Hz) was recorded by Cheron et al. (2008). In a mouse model of Angelman syndrome, they found prominent fast oscillations while recording LFPs, along with single unit activity (Cheron et al., 2004Cheron et al., , 2008 Gall et al., 2005), and confirmed with precision the link of these oscillations with PC activity. In two other recent papers, the existence of these fast oscillations in normal animals has also been confirmed (de Solages et al., 2008; Middleton et al., 2008). ...
... This is the case of the Angelman mouse model, where it appears like the fast (>150 Hz) oscillations in the cerebellar cortex are hypersynchronous for zones up to 1 mm (Cheron et al., 2005), a zone larger than normal fast coherence zones. Some of those fast oscillations are also seen in calretinin/calbindin mutant mice (Cheron et al., 2004Cheron et al., , 2008), affecting the PC layer. In this model, the synchronization of fast oscillations appeared to follow the coronal plane, in line with the parallel fiber orientation, for a range up to 2 mm. ...
In many neuroscience fields, the study of local and global rhythmicity has been receiving increasing attention. These network influences could directly impact on how neuronal groups interact together, organizing for different contexts. The cerebellar cortex harbors a variety of such local circuit rhythms, from the rhythms in the cerebellar cortex per se, or those dictated from important afferents. We present here certain cerebellar oscillatory phenomena that have been recorded in rodents and primates. Those take place in a range of frequencies: from the more known oscillations in the 4-25 Hz band, such as the olivocerebellar oscillatory activity and the granule cell layer oscillations, to the more recently reported slow (<1 Hz oscillations), and the fast (>150 Hz) activity in the Purkinje cell layer. Many of these oscillations appear spontaneously in the circuits, and are modulated by behavioral imperatives. We review here how those oscillations are recorded, some of their modulatory mechanisms, and also identify some of the cerebellar nodes where they could interact. A particular emphasis has been placed on how these oscillations could be modulated by movement and certain neuropathological manifestations. Many of those oscillations could have a definite impact on the way information is processed in the cerebellum and how it interacts with other structures in a variety of contexts.
... In order to explain the emergence of this abnormal rhythm along the parallel fiber beam, the following mechanism has been proposed [164]: the increase of PC rhythmicity facilitates LFP oscillation if already present and the increased LFP oscillation would secondarily recruit rhythmic PCs. This would constitute a positive feedback loop where the fast oscillation is the cause and the consequence of PC synchronicity. ...
... In the physiological situation, small-amplitude 200-Hz activity [162] and PC synchronization at a short distance along the parallel fiber beam are described [163] (small blue arrow). Eventual pathological highfrequency oscillations (large blue arrow) synchronized over a long distance along the parallel fiber beam may disturb the activity of the rostro-caudal modules and the DCN output inducing ataxia [164] ...
The highly stereotyped, crystal-like architecture of the cerebellum has long served as a basis for hypotheses with regard to the function(s) that it subserves. Historically, most clinical observations and experimental work have focused on the involvement of the cerebellum in motor control, with particular emphasis on coordination and learning. Two main models have been suggested to account for cerebellar functioning. According to Llinás's theory, the cerebellum acts as a control machine that uses the rhythmic activity of the inferior olive to synchronize Purkinje cell populations for fine-tuning of coordination. In contrast, the Ito-Marr-Albus theory views the cerebellum as a motor learning machine that heuristically refines synaptic weights of the Purkinje cell based on error signals coming from the inferior olive. Here, we review the role of timing of neuronal events, oscillatory behavior, and synaptic and non-synaptic influences in functional plasticity that can be recorded in awake animals in various physiological and pathological models in a perspective that also includes non-motor aspects of cerebellar function. We discuss organizational levels from genes through intracellular signaling, synaptic network to system and behavior, as well as processes from signal production and processing to memory, delegation, and actual learning. We suggest an integrative concept for control and learning based on articulated oscillation templates.
... The PF was stimulated for Purkinje cells excitation because under physiological conditions, Purkinje cells receive excitatory inputs from mossy fibres. The mossy fibre activates the granule cell, whose axons give rise to the PF, which then form high synaptic contacts at the spines of the distal branch of the Purkinje dendritic tree (Cheron et al., 2008). Harvey and Napper (1991) reported that one Purkinje cell has at least 150,000 PF-Purkinje cell synaptic contacts. ...
Duchenne muscular dystrophy (DMD) is a rapidly progressive X-linked recessive disease affecting about 1 in 3500 live male births. It is caused by mutations in the dystrophin gene, which result in the loss of dystrophin or expression of a non-functional truncated protein product. Full-length dystrophin is mainly expressed in muscles and the central nervous system. In addition to the degeneration of skeletal musculature, about one-third of patients with DMD display various degrees of intellectual impairment, commonly found with intelligence quotient (IQ) scores of one standard deviation below (IQ of 85) the normal population mean (IQ of 100). However, the mechanism underlying the cognitive deficits in DMD remains unclear and no effective treatment is available to reverse this condition in the affected individual. Recent studies showed that the life span of DMD patients today has increased from teens to their fourth decades. With longer survival, the quality of life becomes increasing important. Therefore, research on the cognitive aspect of DMD is as important as research on the muscular aspects because improvements in cognitive function will enhance the quality of life for the growing population of adult DMD patients. The aim of this thesis was to investigate the role of dystrophin in the central nervous system of the mdx mouse, a widely accepted murine model for DMD. This study employed the use of animal with different age groups, corresponding to young (3-4 months), adult (11-12 months), and aged (23-26 months). Adult and aged mdx mice are the focus in this study with findings from the older mouse especially valuable as, disease progression in aged mice closely resembling that of DMD. As numerous evidence has shown a high similarity between the specific cognitive dysfunctions seen in DMD (i.e. impaired verbal intelligence) and in patients with cerebellar lesions (i.e. language disorders), this study examined the function of cerebellar Purkinje cells in mdx mice using electrophysiological recording and calcium imaging. Overall, the data presented in this thesis provides new insights into the role of dystrophin in cerebellar Purkinje neurons. The findings suggest that dystrophin is important for normal inhibitory synaptic function, intrinsic electrophysiological properties, and calcium handling of the mature cerebellar Purkinje cells. The consequences of the absence of dystrophin including the altered GABAA receptor clustering and reduced peak amplitude of mIPSCs could be ameliorated when dystrophin was successfully rescued with Pip6f-PMO in an organotypic mdx cerebellar culture. If mdx mice and DMD patients share similar neuropathogenesis, the development of drugs targeting the altered functions in mdx Purkinje cells may serve as a potential therapy in alleviating the cognitive impairments seen in DMD.
... Our single-neuron recordings captured an oscillation with a center frequency varying 250-300 Hz, very similar to the high-frequency local field potential oscillation (LFPO) described by others in normal rats [10] and a variety of mutant mice [67]. Although such oscillations have been recognized since the earliest recordings of cerebellum using low-impedance electrodes [68], their intensity varies from location to location, and this is the first description of LFPOs in the flocculus. ...
Purkinje cells (PCs) in the cerebellar flocculus carry rate-coded information that ultimately drives eye movement. Floccular PCs lying nearby each other exhibit partial synchrony of their simple spikes (SS). Elsewhere in the cerebellum, PC SS synchrony has been demonstrated to influence activity of the PCs’ synaptic targets, and some suggest it constitutes another vector for information transfer. We investigated in the cerebellar flocculus the extent to which the rate code and PC synchrony interact. One motivation for the study was to explain the cerebellar deficits in ataxic mice like tottering; we speculated that PC synchrony has a positive effect on rate code transmission that is lost in the mutants. Working in transgenic mice whose PCs express channelrhodopsin, we exploited a property of optogenetics to control PC synchrony: pulsed photostimulation engenders stimulus-locked spiking, whereas continuous photostimulation engenders spiking whose timing is unconstrained. We photoactivated flocculus PCs using pulsed stimuli with sinusoidally varying timing vs. continuous stimuli with sinusoidally varying intensity. Recordings of PC pairs confirmed that pulsed stimuli engendered greater PC synchrony. We quantified the efficiency of transmission of the evoked PC firing rate modulation from the amplitudes of firing rate modulation and eye movement. Rate code transmission was slightly poorer in the conditions that generated greater PC synchrony, arguing against our motivating speculation regarding the origin of ataxia in tottering. Floccular optogenetic stimulation prominently augmented a 250–300 Hz local field potential oscillation, and we demonstrate relationships between the oscillation power and the evoked PC synchrony.
... However, in contrast to the memory, LTP was not completely rescued, as revealed via electrophysiology. Additionally, there was not adequate transduction of the transgene into the cerebellum, and, therefore, motor deficits, believed to be associated with this part of the brain, were not improved [24,25]. ...
Introduction
Angelman syndrome is a rare genetic neurodevelopmental disorder, caused by deficiency or abnormal function of the maternal ubiquitin protein-ligase E3A, known as UBE3A, in the central nervous system. Currently, there is no disease-modifying treatment available, but the therapeutic pipeline of Angelman syndrome includes at least 15 mechanistically different approaches at preclinical or clinical development. In the coming years, several clinical trials will be enrolling patients and, therefore, Angelman syndrome community needs to be aware of all options.
Areas covered
In this review, we summarise and critically review the different therapeutic approaches. Some approaches attempt to restore the missing or non-functional UBE3A protein in the neurons via gene replacement or enzyme replacement therapies. Other therapies aim to induce expression of the normal paternal copy of the UBE3A gene by targeting a long non-coding RNA, the UBE3A-ATS, which is believed to interfere with its expression. Another therapeutic category includes compounds that target molecular pathways and effector proteins known to be involved in Angelman syndrome pathophysiology.
Expert Opinion
We believe that by 2022-2023, more than five disease-modifying treatments will be simultaneously at clinical testing. However, the are several challenges with regards to safety and efficacy, which need to be addressed. Additionally, there is still a significant unmet need for clinical trial readiness.
... The present findings in the theta and beta band ranges fit well with the fact that the granular layer of the cerebellum supports low-frequency oscillations ( D'Angelo et al., 2009 ). However, given that the only output of the cerebellar cortex comes from the Purkinje cells in the deep cerebellar nuclei, one might expect to find high-frequency oscillations in the 160-200 Hz range, as have been found in local field potential recordings in mice and humans ( Cheron et al., 2008 ;Dalal et al., 2013 ). Oscillations this fast may make possible the temporal precision on the order of tens of milliseconds found here, and may thus play an important role as well. ...
The cerebellum is involved in predicting the sensory feedback resulting from movements and sensations, but little is known about the precise timing of these predictions due to the scarcity of time-sensitive cerebellar neuroimaging studies. We here, using magnetoencephalography, investigated the hypothesis that one function of the cerebellum is to predict with millisecond precision when rhythmic stimuli are expected to impinge on sensory receptors.
This revealed that omissions following regular trains of stimulation showed higher cerebellar power in the beta band (14-30 Hz) than those following irregular trains of stimulation, within milliseconds of when the omitted stimulus should have appeared. We also found evidence of cerebellar theta band (3-7 Hz) activity encoding the rhythm of new sequences of stimulation.
Our results also strongly suggest that the putamen and the thalamus mirror the cerebellum in showing higher beta band power when omissions followed regular trains of stimulation compared to when they followed irregular trains of stimulation.
We interpret this as the cerebellum functioning as a clock that precisely encodes and predicts upcoming stimulation, perhaps in tandem with the putamen and thalamus. Relative to less predictable stimuli, perfectly predictable stimuli induce greater cerebellar power. This implies that the cerebellum entrains to rhythmic stimuli for the purpose of detecting any deviations from that rhythm.
... Ca 2+ buffers such as calbindin, parvalbumin, and related Ca 2+ -binding proteins l control synaptic strength [113][114][115] and Ca 2+ homeostasis in the presynaptic termina [116]. Calbindin, a rapid Ca 2+ buffer [117], alters short-term synaptic facilitation [118], whereas parvalbumin, a slow Ca 2+ buffer [119], controls decay rate of short-term plasticity [120]. ...
An action potential (AP) triggers neurotransmitter release from synaptic vesicles (SVs) docking to a specialized release site of presynaptic plasma membrane, the active zone (AZ). The AP simultaneously controls the release site replenishment with SV for sustainable synaptic transmission in response to incoming neuronal signals. Although many studies have suggested that the replenishment time is relatively slow, recent studies exploring high speed resolution have revealed SV dynamics with milliseconds timescale after an AP. Accurate regulation is conferred by proteins sensing Ca2+ entering through voltage-gated Ca2+ channels opened by an AP. This review summarizes how millisecond Ca2+ dynamics activate multiple protein cascades for control of the release site replenishment with release-ready SVs that underlie presynaptic short-term plasticity.
... Like in the cerebral cortex, oscillations may provide an excellent long-range communication mechanism within the cerebellum. There is some evidence that oscillations may also be region specific: certain types of oscillations entrain firing in different orientations (e.g., primarily sagittal/anterior-to-posterior axis, patchy, or along the transverse axis) [53] and may be of importance to cognition, as abnormalities in cerebellar oscillatory rhythms have been identified in mouse models of fetal alcohol syndrome [54]. These kinds of intracerebellar communication obviously differ from how sub-regions interact within the PFC and other supratentorial structures. ...
In non-habitual situations, cognitive control aligns actions with both short- and long-term goals. The capacity for cognitive control is tightly tied to the prefrontal cortex, whose expansion in humans relative to other species is thought to support our superior cognitive control. However, the posterolateral cerebellum has also expanded greatly relative to non-human primates and has an organizational structure that mirrors the prefrontal cortex. Nevertheless, cerebellar contributions to cognitive control are poorly understood. Here, we sought to explore whether a functional hierarchical processing framework, applied to the cerebellum, could elucidate cerebellar contributions to cognitive control. Using functional magnetic resonance imaging, we show that a gradient within the posterolateral cerebellum supports cognitive control with motor-adjacent cerebellar sub-regions supporting control of concrete, proximal actions and motor-distal, cerebellar sub-regions supporting abstract, future processing. This gradient was functionally hierarchical, with regions higher in the hierarchy influencing the relationship between regions lower in the hierarchy. This functional hierarchy provides the infrastructure by which context can inform current actions and prepare for future goals. Crucially, this mirrors the hierarchical organization of cognitive control within the prefrontal cortex. Based on these findings, we propose that the cerebellum contains within itself a parallel but separate hierarchical organization that, along with the prefrontal cortex, supports complex cognition.
... Another in vitro data on the properties of CR has been shown that CR in the absence of Ca +2 and even further increased by Ca +2 binding hints that CR might also belong to the sensor function calcium binding proteins [356]. Cheron and colleagues [357] summarized information according to a plasticity at the cerebellum level which is known to be critically associated with calcium signaling and suggest that disruption of cerebellar physiological rhythms could be involved in motor coordination. The existing experimental data from different knockout calretinin, calbindin, parvalbumin mice causes that a 160 Hz local field potential oscillation (LFPO) could lead to cerebellar ataxia, or could reflect the compensatory plasticity that allows the cerebellum to function despite the incorrect firing of cerebellar Purkinje cells. ...
This review assesses the parallel literature on the role of gamma - aminobutyric acid (GABA) in brain plasticity and GABA elements dysfunction related disorders. I review historical and new data from both animal and human sources which have helped define the key role for this transmitter synthesis, release and reuptake, GABA receptors subtype regulation, and GABAergic neurons function in the adult brain. The role of GABAergic elements in neurological and psychiatric disorders is briefly discussed.
... At the cellular, inter-cellular, and network level, neurological systems are incredibly plastic , Turrigiano and Nelson, 2004, Cheron et al., 2008. Perturbations at each level elicit widespread reactions; that can cause long-term alterations in the central nervous system and its functions . ...
Nicotine or ethanol exposure early in development are both risk factors for Sudden Infant Death Syndrome (SIDS). I tested the hypothesis that both nicotine and ethanol may be linked to SIDS by impairing central breathing control responses to low oxygen (hypoxia) and high carbon dioxide (hypercapnia) stressors. Experiments were conducted in bullfrog tadpoles, a model system for respiratory neurotoxicology research. I addressed three specific aims: to characterize the effect of chronic ethanol on central responses to hypercapnia and hypoxia, to characterize the effect of chronic nicotine on central hypoxic responses, and to determine the persistence of hypercapnic impairments following 10-wk exposure to either nicotine or ethanol. 10-wk nicotine exposure resulted in neuroplastic changes that eliminated the central hypoxic responses of early but not late metamorphic tadpoles. Thus, central responses to both hypoxia and hypercapnia were impaired following nicotine exposure. The attenuated central hypercapnic response of nicotine-exposed tadpoles persisted for 1 - 3 wk. Following 10-wk chronic ethanol exposure central responses to hypercapnia and hypoxia were lost regardless of the developmental timing of exposure. Impairments in central hypercapnic responses persisted for 3 - 6 wk after ethanol exposure ended. The recovery of central hypercapnic responses in nicotine- and ethanol-exposed tadpoles may be an example of recuperative neuroplasticity resulting in either a reinstatement of network components and functions or an accommodation to deleterious nicotine- and ethanol-evoked neuroplastic changes. Collectively these data suggest that both nicotine and ethanol may target adaptive and compensatory mechanisms in central breathing control. The teratogen-induced impairments were developmentally dependent in the case of nicotine, and they persisted longer following ethanol exposure. The overall result of exposure to either neuroteratogen was an inability to respond to central breathing stressors, supporting the possible link to SIDS.
http://hdl.handle.net/11122/9025.
... Thus, the electrophysiological recordings of spontaneous firing rate and rhythmicity in vivo provide an efficient way of assessing the functional states of the cerebellar neuronal network, independently of confounding factors, such as the muscle pathology and the reduced body weight of DMSXL mice . Hence, the fast LFP oscillations registered in DMSXL mice revealed pathological changes in integrated Purkinje cell activity (Cheron et al., 2008), which may result from the synchronization of high-frequency rhythmic firing caused by intrinsic Purkinje cell excitability , granular cell hyperexcitability (Bearzatto et al., 2006;, or altered synaptic plasticity (Servais et al., 2007). Abnormal spontaneous fast LFP oscillations were previously reported in ataxic mice showing cerebellum-dependent motor incoordination (Bearzatto et al., 2006;Cheron et al., , 2005Servais et al., 2007), supporting their contribution to the motor phenotype of DMSXL mice in the runway test. ...
Myotonic dystrophy type 1 (DM1) is a severe disorder that affects many tissues, including the central nervous system (CNS). The degree of brain impairment ranges from executive dysfunction, attention deficits, low processing speed, behavioural changes and hypersomnia in the adult form, to pronounced intellectual disability in the congenital cases. The neurological manifestations have a tremendous impact on the academic, professional, social and emotional aspects of daily life. Today there is no cure for this devastating condition. DM1 is caused by the abnormal expansion of a CTG trinucleotide repeat in the 3’UTR of the DMPK gene. Expanded DMPK transcripts accumulate in RNA aggregates (or foci) in the nucleus of DM1 cells, disrupting the activity of important RNA-binding proteins, like the MBNL and CELF families, and leading to abnormalities in alternative splicing, gene expression, RNA polyadenylation, localisation and translation. In spite of recent progress, fundamental gaps in our understanding of the molecular and cellular mechanisms behind the neurological manifestations still exist: we do not know the contribution of each cell type of the CNS to brain dysfunction, or the molecular pathways specifically deregulated in response to the CTG expansion. The aim of my PhD project has been to gain insight into these two important questions using a relevant transgenic mouse model of DM1 and cell cultures derived thereof. In my studies I used the DMSXL mice, previously generated in my host laboratory. The DMSXL mice express expanded DMPK mRNA with more than 1,000 CTG repeats. They recreate relevant DM1 features, such as RNA foci and missplicing in multiple tissues. The functional impact of expanded DMPK transcripts in the CNS of DMSXL mice translates into behavioural and cognitive abnormalities and defective synaptic plasticity. To identify the molecular mechanisms behind these abnormalities, a global proteomics analysis revealed changes in both neuron-specific and glial-specific proteins in DMSXL brain. We also investigated RNA foci in DMSXL and human DM1 brains and found non-homogenous distribution between cell types, with a higher foci content in astrocytes relative to neurons. Together these results suggest that both neuronal and glial defects contribute to DM1 neuropathogenesis. The global proteomics analysis of DMSXL brains also identified abnormalities in neuronal synaptic proteins that we have validated in human brain samples. SYN1 is hyperphosphorilated in a CELF-dependent manner while RAB3A is upregulated in association with MBNL1 depletion. CELF and MBNL proteins regulate the alternative splicing of a subset of transcripts throughout development, and their deregulation in DM1 leads to abnormal expression of fetal splicing isoforms in adult DM1 brains. In this context, I have studied if RAB3A and SYN1 deregulations observed in adult brains are associated with splicing abnormalities or if they recreated embryonic expression and phosphorylation events. My results indicate that the synaptic proteins abnormalities observed in adult DMSXL brains are not caused by defective alternative splicing and do not recreate embryonic events. Thus, DM1 neuropathogenesis goes beyond missplicing and other molecular pathways must be explored in DM1 brains. To better understand the cellular sub-populations susceptible of accumulating toxic RNA foci we have studied foci distribution in different brain regions. We identified pronounced accumulation of toxic RNAs in Bergman astrocytes of DMSXL mice cerebellum and DM1 patients, associated with neuronal hyperactivity of Purkinje cells. A quantitative proteomics analysis revealed a significant downregulation of GLT1 – a glial glutamate transporter expressed by the Bergmann cell in the cerebellum. I have confirmed the GLT1 downregulation in other brain regions of mouse and human brain. (...)
... In the presynaptic terminal Ca 2+ buffers such as parvalbumin, calbindin, and related Ca 2+ -binding proteins control Ca 2+ homeostasis [139] and synaptic strength [140][141][142]. A slow Ca 2+ buffer parvalbumin [143] controls decay rate of short-term plasticity [144]. ...
... In the presynaptic terminal Ca 2+ buffers such as parvalbumin, calbindin, and related Ca 2+ -binding proteins control Ca 2+ homeostasis [139] and synaptic strength [140][141][142]. A slow Ca 2+ buffer parvalbumin [143] controls decay rate of short-term plasticity [144]. ...
Presynaptic Ca2+ entry occurs through voltage-gated Ca2+ (CaV) channels which are activated by membrane depolarization. Depolarization accompanies neuronal firing and elevation of Ca2+ triggers neurotransmitter release from synaptic vesicles. For synchronization of efficient neurotransmitter release, synaptic vesicles are targeted by presynaptic Ca2+ channels forming a large signaling complex in the active zone. The presynaptic CaV2 channel gene family (comprising CaV2.1, CaV2.2, and CaV2.3 isoforms) encode the pore-forming α1 subunit. The cytoplasmic regions are responsible for channel modulation by interacting with regulatory proteins. This article overviews modulation of the activity of CaV2.1 and CaV2.2 channels in the control of synaptic strength and presynaptic plasticity.
... Paired recordings in vivo have shown that the firing of neighboring PCs is sometimes correlated on rapid timescales (Bell and Grimm, 1969;Bell and Kawasaki, 1972;de Solages et al., 2008;De Zeeuw et al., 1997;Ebner and Bloedel, 1981;Shin and De Schutter, 2006). It is also thought that correlated PC firing underlies high-frequency oscillations in LFPs in the cerebellar cortex (Adrian, 1935;Cheron et al., 2004Cheron et al., , 2008Courtemanche et al., 2013;de Solages et al., 2008;Groth and Sahin, 2015;Middleton et al., 2008;Oehler et al., 1969). Several possible mechanisms have been advanced to account for correlated firing, including shared excitatory inputs (Bell and Grimm, 1969;Ebner and Bloedel, 1981;Heck et al., 2007;Isope et al., 2002), inhibition provided by PC axon collaterals (de Solages et al., 2008;Witter et al., 2016), and gap junction coupling Traub et al., 2008). ...
Correlated neuronal activity at various timescales plays an important role in information transfer and processing. We find that in awake-behaving mice, an unexpectedly large fraction of neighboring Purkinje cells (PCs) exhibit sub-millisecond synchrony. Correlated firing usually arises from chemical or electrical synapses, but, surprisingly, neither is required to generate PC synchrony. We therefore assessed ephaptic coupling, a mechanism in which neurons communicate via extracellular electrical signals. In the neocortex, ephaptic signals from many neurons summate to entrain spiking on slow timescales, but extracellular signals from individual cells are thought to be too small to synchronize firing. Here we find that a single PC generates sufficiently large extracellular potentials to open sodium channels in nearby PC axons. Rapid synchronization is made possible because ephaptic signals generated by PCs peak during the rising phase of action potentials. These findings show that ephaptic coupling contributes to the prevalent synchronization of nearby PCs.
... Parvalbumin, calbindin, and related calcium-binding proteins are expressed at high levels in many cell types, where they control calcium transients, participate in calcium signaling pathways, and are protective against calcium overload (Schwaller, 2010). Experiments at several types of synapses indicate that loss of these calciumbinding proteins modulates synaptic plasticity and homeostatic regulation of synaptic strength (Cheron et al., 2008;Chevaleyre and Piskorowski, 2014;Gainey and Feldman, 2017). If calcium entry in response to the first action potential in a pair saturates local calcium buffers, calcium entry during a second action potential may elicit a larger intracellular calcium transient because entering calcium is less effectively buffered and thereby could induce rapid short-term facilitation as well as slower forms of synaptic plasticity. ...
Voltage-gated calcium channels couple depolarization of the cell-surface membrane to entry of calcium, which triggers secretion, contraction, neurotransmission, gene expression, and other physiological responses. They are encoded by ten genes, which generate three voltage-gated calcium channel subfamilies: CaV1; CaV2; and CaV3. At synapses, CaV2 channels form large signaling complexes in the presynaptic nerve terminal, which are responsible for the calcium entry that triggers neurotransmitter release and short-term presynaptic plasticity. CaV1 channels form signaling complexes in postsynaptic dendrites and dendritic spines, where their calcium entry induces long-term potentiation. These calcium channels are the targets of mutations and polymorphisms that alter their function and/or regulation and cause neuropsychiatric diseases, including migraine headache, cerebellar ataxia, autism, schizophrenia, bipolar disorder, and depression. This article reviews the molecular properties of calcium channels, considers their multiple roles in synaptic plasticity, and discusses their potential involvement in this wide range of neuropsychiatric diseases.
... Thus, the electrophysiological recordings of spontaneous firing rate and rhythmicity in vivo provide an efficient way of assessing the functional states of the cerebellar neuronal network, independently of confounding factors, such as the muscle pathology and the reduced body weight of DMSXL mice (Gomes-Pereira et al., 2007;Huguet et al., 2012). Hence, the fast LFP oscillations registered in DMSXL mice revealed pathological changes in integrated Purkinje cell activity (Cheron et al., 2008), which may result from the synchronization of high-frequency rhythmic firing caused by intrinsic Purkinje cell excitability (Cheron et al., 2004), granular cell hyperexcitability (Bearzatto et al., 2006;Cheron et al., 2004), or altered synaptic plasticity (Servais et al., 2007). Abnormal spontaneous fast LFP oscillations were previously reported in ataxic mice showing cerebellum-dependent motor incoordination (Bearzatto et al., 2006;Cheron et al., 2004Cheron et al., , 2005Servais et al., 2007), supporting their contribution to the motor phenotype of DMSXL mice in the runway test. ...
Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels.
... Many mutations that cause cerebellum degeneration result in an ataxic phenotype (Chakrabarti et al. 2008;Cheron et al. 2008;Dusart et al. 2006;Harkins and Fox 2002;Millen and Gleeson 2008). The ataxia of Chd6 Exon 12 -/-mice is not noticeably progressive and does not change significantly with age. ...
... FUNCTIONAL FEATURES OF CALCIUM-BINDING PROTEINS CR plays an important role in the regulation of cell excitability and the synaptic plasticity processes, in particular, the induction of LTP in hippocampal neurons [22]. Mutant mice that do not contain CR exhibit changes in functional characteristics of CNS neurons, in particular, an increased frequency of impulses of Purkinje cells and shorter interspike intervals [24,25]. A decrease in CR-immunopositive neurons was observed in Huntington's disease [49]. ...
Calbindin 28 kDa (CB), calretinin (CR), and parvalbumin (PB) are calcium-binding proteins that are widely distributed in the nervous system and selectively expressed in certain population of neurons. These proteins are expressed not only in the central nervous system but also the autonomic ganglia. CB and PB are found in the sympathetic ganglia of rodents, and CB and CR are found in metasympathetic intramural ganglia. Their functions are poorly understood, but one can suggest that they have an important role in the regulation of Ca²⁺ levels in the cell. Calcium-binding proteins also play an important role in the age-related development of autonomic neurons. The percentage of CB- and CR-immunopositive neurons in the metasympathetic intramural ganglia of the small intestine in early postnatal development increases, whereas the percentage of CB decreases in sympathetic ganglia. It is possible that the functional meaning of such changes may be associated with the role of calcium currents in the development of neurons and the synaptic transmission.
... [3][4][5] According to this perspective, the cerebellum is believed to exert a regulatory function that enhances and supplements other brain functions, through direct and indirect circuits. 2 Moreover, different sources of evidence have suggested that the cerebellum may be altered in many psychiatric disorders, including schizophrenia, 6 bipolar disorder (BD), 7 unipolar depression, 8 anxiety, 9 and attention deficit hyperactivity disorder. 10 In some reports, cerebellar deficits were described as isolated findings, without any relationship with clinical history whereas others show evidence that the cerebellum is a relevant brain structure possibly related to a range of psychopathological manifestations. ...
Objective:
In this research, the goal was to measure the volume of the cerebellum and its subregions in individuals with psychiatric disorders and to relate these findings to their symptoms.
Methods:
Patients with different degrees of cognitive impairment (Epidemiology of the Elderly - UNIFESP) and patients with post-traumatic stress disorder (PTSD) from population studies were analyzed. Also, patients with bipolar disorder from an outpatient clinic (Center for the Study of Mood and Anxiety Disorders, Universidade Federal da Bahia) were recruited for this study. All subjects underwent a 1.5T structural magnetic resonance scan. Volumetric measures and symptom measurements, by psychometric scales, were performed and compared between patients and controls.
Results:
The cerebellum volume was reduced in patients with cognitive impairment without dementia and with dementia, in patients with PTSD, and in patients with bipolar disorder compared to controls. In dementia and PTSD, the left cerebellar hemisphere and vermis volume were reduced. In bipolar disorder, volumes of both hemispheres and the vermis were reduced. In the first two studies, these cerebellar volumetric reductions correlated with symptoms of the disease.
Conclusion:
The exact nature of cerebellar involvement in mental processes is still not fully understood. However, abnormalities in cerebellar structure and its functions have been reported in some of these diseases. Future studies with larger samples are needed to clarify these findings and investigate whether they are important for treatment and prognosis.
... Thus, the electrophysiological recordings of spontaneous firing rate and rhythmicity in vivo provide an efficient way of assessing the functional states of the cerebellar neuronal network, independently of confounding factors, such as the muscle pathology and the reduced body weight of DMSXL mice (Gomes-Pereira et al., 2007;Huguet et al., 2012). Hence, the fast LFP oscillations registered in DMSXL mice revealed pathological changes in integrated Purkinje cell activity (Cheron et al., 2008), which may result from the synchronization of high-frequency rhythmic firing caused by intrinsic Purkinje cell excitability (Cheron et al., 2004), granular cell hyperexcitability (Bearzatto et al., 2006;Cheron et al., 2004), or altered synaptic plasticity (Servais et al., 2007). Abnormal spontaneous fast LFP oscillations were previously reported in ataxic mice showing cerebellum-dependent motor incoordination (Bearzatto et al., 2006;Cheron et al., 2004Cheron et al., , 2005Servais et al., 2007), supporting their contribution to the motor phenotype of DMSXL mice in the runway test. ...
... By now, the physiological role of the cerebellum in behavioral learning has become an issue largely treated at several levels, including functional, cellular, and molecular aspects. Bidirectional interactions with the environment refine the neural circuitry that involves the cerebellum, thus ensuring a fine-tuned functioning of this structure (Cheron et al. 2008). In addition, the notable cerebellar capability to compensate for lesion-induced deficits is also demonstrated. ...
Neuroplasticity allows the brain to encode experience and learn behaviors, and also to re-acquire lost functions after damage. The cerebellum is a suitable structure to address this topic because of its strong involvement in learning processes and compensation of lesion-induced deficits. This study was aimed to characterize the effects of a hemicerebellectomy (HCb) combined or not with the exposition to environmental enrichment (EE) on dendritic spine density and size in Purkinje cell proximal and distal compartments of cerebellar vermian and hemispherical regions. Male Wistar rats were housed in enriched or standard environments from the 21st post-natal day (pnd) onwards. At the 75th pnd, rats were submitted to HCb or sham lesion. Neurological symptoms and spatial performance in the Morris water maze were evaluated. At the end of testing, morphological analyses assessed dendritic spine density, area, length, and head diameter on vermian and hemispherical Purkinje cells. All hemicerebellectomized (HCbed) rats showed motor compensation, but standard-reared HCbed animals exhibited cognitive impairment that was almost completely compensated in enriched HCbed rats. The standard-reared HCbed rats showed decreased density with augmented size of Purkinje cell spines in the vermis, and augmented both density and size in the hemisphere. Enriched HCbed rats almost completely maintained the spine density and size induced by EE. Both lesion-induced and activity-dependent cerebellar plastic changes may be interpreted as "beneficial" brain reactions, aimed to support behavioral performance rescuing.
... Calretinin plays an important role in regulating the level of cell excitability and synaptic transmission process-es, particularly the induction of long-term potentiation in hippocampal neurons [26]. Mutant mice lacking calretinin showed changes in the functional characteristics of neurons in the central nervous system, particularly an increase in the spike frequency of Purkinje cells, with shorter interspike intervals [32]. ...
Sensory neurons represent various groups of neurons differ on their morphological, immunohistochemical and receptor characteristics. The most of large neurons with myelinated Aδ fibers contain neurofilament 200 (NF200), some small afferent neurons can bind the isolectin B4 (IB4). Also, sensory neurons may include different types of tyrosine kinases (trkA, B and C) and neurotransmitters. Neuropeptides are generally located in small and medium-sized neurons. The proportion of neurons which contain trkA decreases and the percentage of NF200-, IB4-, substance P- and CGRP-positive neurons increases during the early development. Development of different types of sensory neurons fulfill under control of neurotrophins.
... They appeared during preparation for goal directed movements but not during non-goal directed repetitive movements. These high frequency field potentials have been shown to originate from the Purkinje cell layer and are believed to be the result of Purkinje cell simple spike synchrony (Cheron et al., 2004(Cheron et al., , 2008de Solages et al., 2008;Middleton et al., 2008). There are several theories as to how this spike synchrony arises. ...
The cerebellum is involved in sensory-motor integration and cognitive functions. The origin and function of the field potential oscillations in the cerebellum, especially in the high frequencies, have not been explored sufficiently. The primary objective of this study was to investigate the spatio-temporal characteristics of high frequency field potentials (150-350 Hz) in the cerebellar cortex in a behavioral context. To this end, we recorded from the paramedian lobule in rats using micro electro-corticogram (μ-ECoG) electrode arrays while the animal performed a lever press task using the forelimb. The phase synchrony analysis shows that the high frequency oscillations recorded at multiple points across the paramedian cortex episodically synchronize immediately before and desynchronize during the lever press. The electrode contacts were grouped according to their temporal course of phase synchrony around the time of lever press. Contact groups presented patches with slightly stronger synchrony values in the medio-lateral direction, and did not appear to form parasagittal zones. The size and location of these patches on the cortical surface are in agreement with the sensory evoked granular layer patches originally reported by Welker's lab (Shambes et al., 1978). Spatiotemporal synchrony of high frequency field potentials has not been reported at such large-scales previously in the cerebellar cortex.
... Calretinin plays an important role in regulating the level of cell excitability and synaptic transmission process-es, particularly the induction of long-term potentiation in hippocampal neurons [26]. Mutant mice lacking calretinin showed changes in the functional characteristics of neurons in the central nervous system, particularly an increase in the spike frequency of Purkinje cells, with shorter interspike intervals [32]. ...
Sensory neurons constitute a heterogeneous population of neurons with different morphological, receptor, and immunohistochemical characteristics. Most large neurons with myelinated fibers of the Aδ group contain 200-kDal neurofilament protein (NF200), while some small afferent intervertebral ganglion neurons can bind isolectin B4 (IB4). Sensory neurons can contain different types of tyrosine kinase (A, B, and C) and have different neurotransmitter compositions. Neuropeptides are found mainly in neurons of small and intermediate size. The proportion of neurons containing tyrosine kinase A decreases and the proportions of neurons positive for NF200, IB4, substance P, and CGRP increase during early postnatal ontogeny. The growth and development of sensory neurons, especially during the embryonic period, occurs under the influence of neurotrophins.
... Calretinin plays an important role in the regulation of the excitability level of the cell and the processes of synaptic plasticity, in particular, the induction of LTP in hippocampal neurons [26]. In calretinin knockout mice, changes in the functional characteristics of CNS neurons in particular increased the firing rate of Purkinje cells, and decreased interspike intervals were observed [32]. ...
Sensory neurons represent various groups of neurons differ on their morphological, immunohistochemical and receptor characteristics. The most of large neurons with myelinated Adelta fibers contain neurofilament 200 kD (NF200), some small afferent neurons can bind the isolectin B4 (IB4). Also, sensory neurons may include different types of tyrosine kinases (trkA, B and C) and neurotransmitters. Neuropeptides are generally located in small and medium-sized neurons. The proportion of neurons which contain trkA decreases and the percentage of NF200-, IB4-,substance P- and CGRP-positive neurons increases during the early development. Development of different types of sensory neurons fulfill under control of neurotrophins.
... Aberrations in the above signaling steps or in the control of intracellular Ca 2+ levels would be expected to impair LTD regulation and malfunction of PC output. Indeed, deficiencies in calcium-binding proteins -such as calretinin, calbindin, and parvalbumin -disturb PC firing [24] and impair LTD. However, our knowledge of the molecular players that regulate the components of the signaling feedback loop that leads to AMPAR internalization and cerebellar LTD is still limited. ...
Background
Regulation of synaptic connectivity, including long-term depression (LTD), allows proper tuning of cellular signalling processes within brain circuitry. In the cerebellum, a key centre for motor coordination, a positive feedback loop that includes mitogen-activated protein kinases (MAPKs) is required for proper temporal control of LTD at cerebellar Purkinje cell synapses. Here we report that the tyrosine-specific MAPK-phosphatase PTPRR plays a role in coordinating the activity of this regulatory loop.ResultsLTD in the cerebellum of Ptprr ¿/¿ mice is strongly impeded, in vitro and in vivo. Comparison of basal phospho-MAPK levels between wild-type and PTPRR deficient cerebellar slices revealed increased levels in mutants. This high basal phospho-MAPK level attenuated further increases in phospho-MAPK during chemical induction of LTD, essentially disrupting the positive feedback loop and preventing ¿-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) phosphorylation and endocytosis.Conclusions
Our findings indicate an important role for PTPRR in maintaining low basal MAPK activity in Purkinje cells. This creates an optimal `window¿ to boost MAPK activity following signals that induce LTD, which can then propagate through feed-forward signals to cause AMPAR internalization and LTD.
... Prevalence of autistic disorder is still debated, possibly in relation to discrepancies in interpretation of autistic-like features. Research on animal models has already yielded valuable insights into other features of Angelman syndrome, including some areas of cognition, motor control, epilepsy, sleep, and electrophysiology (Jiang et al 1998;Delorey et al 1998;Miura et al 2002;Weeber et al 2003;Cheron et al 2005Cheron et al , 2008Colas et al 2005;Handforth et al 2005;van Woerden et al 2007;Ferguson et al 2007). More specifi c study of behavior is still needed. ...
Angelman syndrome has been suggested as a disease model of neurogenetic developmental condition with a specific behavioral phenotype. It is due to lack of expression of the UBE3A gene, an imprinted gene located on chromosome 15q. Here we review the main features of this phenotype, characterized by happy demeanor with prominent smiling, poorly specific laughing and general exuberance, associated with hypermotor behavior, stereotypies, and reduced behavioral adaptive skills despite proactive social contact. All these phenotypic characteristics are currently difficult to quantify and have been subject to some differences in interpretation. For example, prevalence of autistic disorder is still debated. Many of these features may occur in other syndromic or nonsyndromic forms of severe intellectual disability, but their combination, with particularly prominent laughter and smiling may be specific of Angelman syndrome. Management of problematic behaviors is primarily based on behavioral approaches, though psychoactive medication (eg, neuroleptics or antidepressants) may be required.
... In the experiments on cerebellar mutant mice, high-frequency synchrony (>150 Hz) was shown in the zones up to 1 mm (Servais and Cheron, 2005). Some of these oscillations were also noted in calretinin/calbindin mutant mice along the parallel fiber orientations ranging up to 2 mm (Servais et al., 2004;Cheron et al., 2008). These reports support the spatial synchrony that we observe in our recordings, although the area covered by our MEA was unprecedented in size (300 µm-2100 µm). ...
The changes of excitability in affected neural networks can be used as a marker to study the temporal course of traumatic brain injury (TBI). The cerebellum is an ideal platform to study brain injury mechanisms at the network level using the electrophysiological methods. Within its crystalline morphology, the cerebellar cortex contains highly organized topographical subunits that are defined by two main inputs, the climbing (CFs) and mossy fibers (MFs). Here we demonstrate the use of cerebellar evoked potentials (EPs) mediated through these afferent systems for monitoring the injury progression in a rat model of fluid percussion injury (FPI). A mechanical tap on the dorsal hand was used as a stimulus, and EPs were recorded from the paramedian lobule (PML) of the posterior cerebellum via multi-electrode arrays (MEAs). Post-injury evoked response amplitudes (EPAs) were analyzed on a daily basis for 1 week and compared with pre-injury values. We found a trend of consistently decreasing EPAs in all nine animals, losing as much as 72 ± 4% of baseline amplitudes measured before the injury. Notably, our results highlighted two particular time windows; the first 24 h of injury in the acute period and day-3 to day-7 in the delayed period where the largest drops (~50% and 24%) were observed in the EPAs. In addition, cross-correlations of spontaneous signals between electrode pairs declined (from 0.47 ± 0.1 to 0.35 ± 0.04, p < 0.001) along with the EPAs throughout the week of injury. In support of the electrophysiological findings, immunohistochemical analysis at day-7 post-injury showed detectable Purkinje cell loss at low FPI pressures and more with the largest pressures used. Our results suggest that sensory evoked potentials (SEPs) recorded from the cerebellar surface can be a useful technique to monitor the course of cerebellar injury and identify the phases of injury progression even at mild levels.
... [3][4][5] According to this perspective, the cerebellum is believed to exert a regulatory function that enhances and supplements other brain functions, through direct and indirect circuits. 2 Moreover, different sources of evidence have suggested that the cerebellum may be altered in many psychiatric disorders, including schizophrenia, 6 bipolar disorder (BD), 7 unipolar depression, 8 anxiety, 9 and attention deficit hyperactivity disorder. 10 In some reports, cerebellar deficits were described as isolated findings, without any relationship with clinical history whereas others show evidence that the cerebellum is a relevant brain structure possibly related to a range of psychopathological manifestations. ...
... Hecho único en todo el sistema nervioso central, la CP adulta sólo recibe información de una sola fibra ascendente, que forma contactos sinápticos «pasando» por la arborización dendrítica de la CP y produciendo una potente activación que implica la activación de los canales Ca 2+ dependientes de voltaje. Se ha demostrado recientemente el papel fundamental de la homeostasis del ion Ca 2+ en las neuronas del cerebelo en diferentes ratones deficientes en proteínas, ligando el Ca 2+ y produciendo la emergencia de la oscilación rápida de la corteza cerebelosa, lo cual produce trastornos de la coordinación motora [25] . De forma espontánea, las CP son a menudo activadas y descargan potenciales de acción de forma simple (simple spike) de modo irregular con una frecuencia de 50 Hz. ...
La neurofisiología del movimiento y del aprendizaje motor cubre un terreno científico muy amplio. Las bases fundamentales de la elaboración central del movimiento están inscritas en unas estructuras cerebrales muy específicas en el plano anatómico y funcional, pero están también muy ricamente interconectadas formando conjuntos neuronales jerarquizados y dinámicos. El objetivo principal de este artículo consiste en introducir las bases generales del aprendizaje motor obtenidas gracias a experimentos realizados a partir de modelos animales elementales con el fin de integrarlos progresivamente en comportamientos motores más complejos. Las bases del aprendizaje neuronal que implican la potenciación y la depresión a largo plazo y los mecanismos localizados a nivel de la membrana de las neuronas, así como aquellos que activan el material genético neuronal, están considerados en su contexto experimental inicial antes de ser descritos en el campo de comportamientos motores más complejos que implican principalmente la motricidad humana. Se propone una visión actualizada de los diferentes sistemas corticales y subcorticales, base de la neurofisiología del movimiento y de su plasticidad. La estructura dinámica propuesta integra las áreas corticales implicadas en la organización de la actividad voluntaria y de la dirección sensorial, así como el papel de los núcleos de la base y del cerebelo. La descripción de las neuronas espejo y del modelo interno debería permitir comprender mejor la dinámica general de la actividad motora y de su aprendizaje.
... For example, we have recently reported that ethanol-enhanced oscillatory discharge patterns are present in cerebellar GoCs [11]. Synchronized patterns of firing have also been reported in GoCs located several millimeter from each other [12,13] and regular, tonic discharge patterns in cerebellar PCs have been linked to oscillations in local field potentials [14,15]. Many individual PCs may engage in synchronized firing as they converge onto a single deep cerebellar nucleus cell. ...
Neuronal oscillations have been shown to contribute to the function of the cerebral cortex by coordinating the neuronal activities of distant cortical regions via a temporal synchronization of neuronal discharge patterns. This can occur regardless whether these regions are linked by cortico-cortical pathways or not. Less is known concerning the role of neuronal oscillations in the cerebellum. Golgi cells and Purkinje cells are both principal cell types in the cerebellum. Purkinje cells are the sole output cells of the cerebellar cortex while Golgi cells contribute to information processing at the input stage of the cerebellar cortex. Both cell types have large cell bodies, as well as dendritic structures, that can generate large currents. The discharge patterns of both these cell types also exhibit oscillations. In view of the massive afferent information conveyed by the mossy fiber-granule cell system to different and distant areas of the cerebellar cortex, it is relevant to inquire the role of cerebellar neuronal oscillations in information processing. In this study, we compared the discharge patterns of Golgi cells and Purkinje cells in conscious rats and in rats anesthetized with urethane. We assessed neuronal oscillations by analyzing the regularity in the timing of individual spikes within a spike train by using autocorrelograms and fast-Fourier transform. We measured the differences in neuronal oscillations and the amount of information content in a spike train (defined by Shannon entropy processed per unit time) in rats under anesthesia and in conscious, awake rats. Our findings indicated that anesthesia caused more prominent neuronal oscillations in both Golgi cells and Purkinje cells accompanied by decreases in Shannon information entropy in their spike trains.
... In the cerebellum, however, Purkinje cells (PCs) appear affected in G3BP1 KO mice, as there was a slight Purkinje cells degeneration (assessed visually and by counting the number of Purkinje cells, PCs, by lm, with a p-value of 0.1) (Fig. 2b, lower right panel). Given that no anomalies were detected in muscles or motor neurons from G3BP1 KO mice and that PCs are the sole output of the cerebellum involved in the control of motor activity (Cheron et al. 2008 ), the ataxialike phenotype might be linked to cerebellum dysfunction. However, other motor-related brain regions may also be involved in this phenotype and need to be further studied. ...
... In Chapter 3.2 we describe how regular patterns coincide in nearby Purkinje cells, without precise simple spike synchronization. Additional support could be considered to come from studies demonstrating the occurrence of (low to very high frequency) oscillations in the cerebellar cortex (Middleton and Strick, 1994;Courtemanche and Lamarre, 2005;de Solages et al., 2008;Van Der Giessen et al., 2008), but the enhanced oscillations in an ataxic mouse mutant could be interpreted as contradictory support (as reviewed by Cheron et al., 2008;. ...
This thesis focuses on the control of the cerebellum on motor behaviour, and more
specifically on the role of the cerebellar Purkinje cells in exerting this control. As the
cerebellum is an online control system, we look at both motor performance and learning,
trying to identify components involved at the molecular, cellular and network level.
To study the cerebellum we used the vestibulocerebellum, with visual and
vestibular stimulation as input and eye movements as recorded output. The advantage
of the vestibulocerebellum over other parts is that the input given is highly controllable,
while the output can be reliably measured, and performance and learning can be easily
studied. In addition, we conducted electrophysiological recordings from the vestibulocerebellum,
in particular of Purkinje cells in the flocculus. Combining the spiking
behaviour of Purkinje cells with visual input and eye movement output allowed us to
study how the cerebellum functions and using genetically modified animals we could
determine the role of different elements in this system.
To provide some insights in the techniques used and the theory behind them, we
will discuss the following topics in this introduction: compensatory eye movements,
the anatomy of pathways to, within and out of the flocculus, the cellular physiology of
Purkinje cells in relation to performance and the plasticity mechanisms related to motor
learning.
... Calretinin was suggested to have a role in the maintenance of calcium dynamics and neuronal excitability (Edmonds et al., 2000;Gall et al., 2003;Camp and Wijesinghe, 2009). Although there are significant data associating calretinin with the mechanisms of neuroplasticity (Schurmans et al., 1997;Gurden et al., 1998;Cheron et al., 2008), here in this work it could not be found substantial differences in the CR1 networks in the IPL of dim-light-reared animals. Furthermore, no statistically differences were seen in calretinin western-blotting analyses, although a slight tendency at P9 and P12 was seen in the retinas of dim-light-reared chickens. ...
Members of the family of calcium binding proteins (CBPs) are involved in the buffering of calcium (Ca2+) by regulating how Ca2+ can operate within synapses or more globally in the entire cytoplasm and they are present in a particular arrangement in all types of retinal neurons. Calbindin D28k and calretinin belong to the family of CBPs and they are mainly co-expressed with other CBPs. Calbindin D28k is expressed in doubles cones, bipolar cells and in a subpopulation of amacrine and ganglion neurons. Calretinin is present in horizontal cells as well as in a subpopulation of amacrine and ganglion neurons. Both proteins fill the soma at the inner nuclear layer and the neuronal projections at the inner plexiform layer. Moreover, calbindin D28k and calretinin have been associated with neuronal plasticity in the central nervous system. During pre and early postnatal visual development, the visual system shows high responsiveness to environmental influences. In this work we observed modifications in the pattern of stratification of calbindin immunoreactive neurons, as well as in the total amount of calbindin through the early postnatal development. In order to test whether or not calbindin is involved in retinal plasticity we analyzed phosphorylated p38 MAPK expression, which showed a decrease in p-p38 MAPK, concomitant to the observed decrease of calbindin D28k. Results showed in this study suggest that calbindin is a molecule related with neuroplasticity, and we suggest that calbindin D28k has significant roles in neuroplastic changes in the retina, when retinas are stimulated with different light conditions. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013.
... In the cerebellum, however, Purkinje cells (PCs) appear affected in G3BP1 KO mice, as there was a slight Purkinje cells degeneration (assessed visually and by counting the number of Purkinje cells, PCs, by lm, with a p-value of 0.1) (Fig. 2b, lower right panel). Given that no anomalies were detected in muscles or motor neurons from G3BP1 KO mice and that PCs are the sole output of the cerebellum involved in the control of motor activity (Cheron et al. 2008), the ataxialike phenotype might be linked to cerebellum dysfunction. However, other motor-related brain regions may also be involved in this phenotype and need to be further studied. ...
Ras-GAP SH3 domain binding protein, G3BP, is an important component in the assembly of stress granules (SGs) which are cytoplasmic aggregates assembled following translational stress. To assess the physiological function of G3BP, we generated viable G3bp1-knockout (KO) mice, which demonstrated behavioral defects linked to the central nervous system (CNS) associated with ataxia phenotype. Immunohistochemistry pinpointed high expression of G3BP in the cytoplasm of hippocampal neurons and Purkinje cells of the cerebellum of wild-type (WT) mice. Also, electrophysiological measurements revealed that the absence of G3BP1 leads to an enhancement of short-term potentiation (STP) and long-term depression (LTD) in the CA1 area of G3bp1 KO mice compared to WT mice. Consistently, G3BP1-deficiency in neurons leads to an increase in intracellular calcium and calcium release in response to (S)-3,5-Dihydroxyphenylglycine (DHPG), a selective agonist of group I metabotropic glutamate receptors. These results show for the first time a requirement for G3BP1 in the control of neuronal plasticity and calcium homeostasis and further establish a direct link between SG formation and neurodegenerative diseases. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12189.
Ca2+ is an important ion in central nervous system (CNS) biology, where it plays a critical role in the basic functions of neurons, glia, and other cell types. In CNS neurons, Ca2+ is a generator of electrical signals, an inducer and regulator of synaptic transmission, and a second messenger that controls many biochemical processes. Ca2+ is also a signal transmitter and second messenger in glial cells. Ca2+ levels in neurons and glia are dynamic but judiciously controlled in order to maintain biological processes at a level compatible with life. An excess or deficit of Ca2+ can result in cell damage or death. A variety of cellular mechanisms, through a process referred to as Ca2+ signaling, enable or contribute to the changes in intracellular Ca2+ that are essential for normal cell function, some of which are present in all eukaryotic cells and others that are unique to the functions of a particular class of cells. This chapter will briefly describe the cellular mechanisms that contribute to Ca2+ signaling in cerebellar and other CNS neurons. These mechanisms are located throughout the neuron including at presynaptic sites (e.g., axon terminals) where they regulate transmitter release, at postsynaptic sites (e.g., dendrites) where they influence synaptic responses, in the cytosol where they regulate biochemical pathways and other physiological functions, and in the nucleus where they regulate gene transcription. Many of these mechanisms are also expressed in non-neuronal cells.KeywordsCa2+ signalingSecond messengersIntracellular Ca2+ storesCa2+ channelsligand-gated receptorsCa2+-binding proteins
One of the essential characteristics that differentiate animal and plant species is their ability to move in space. It thus appears that motor skills condition the development of cognition. In this respect, the present thesis begins with a triple observation, that: (1) attention is subordinated to action, (2) there is an intimate relationship between attentional control and sensorimotor control through the exercise of sustained attention, and (3) there is a second (inverse) relationship between attentional control and sensorimotor control through the exercise of stillness. Through work on brain electrophysiology in different attentional conditions - action observation, attention deficit (with or without hyperactivity), and mindfulness meditation - the present thesis aims to contribute to the identification of brain dynamics underlying attentional control and the ways in which the exercise of this control can, in turn, modulate the brain's procedural activities. After a detailed review of the fundamental properties of attention, the general principles of electroencephalogram, and the neural correlates underlying attentional control, we preliminarily focused on the oscillatory dynamics associated with visual attention. From an experimental point of view, the aim was to distinguish the different functional components (visual, attentional, sensorimotor) of the brain rhythms by modifying the visual information (an animation of walking) passively submitted to the subject's attention. On this basis, we next explored brain dynamics in children with attention deficit (with/without hyperactivity, ADHD) during an attention/inhibition task (Cue-GO/NoGO). We showed an alteration of the rhythms linked to the processing of visual information. From a neuroanatomical point of view, our data indicated that this deficit would be based on an imbalance between the two fronto-parietal attention systems, ventral-medial and dorso-lateral, which could make these children more sensitive to the salience of visual information and induce less flexibility in cognitive control. In contrast, we showed that the 'non-reactive' dimension of mindfulness altered the temporal dynamics of large-scale neural networks. This effect appeared to be support by increased cerebellum activity, and to induce less (re)activity of the attentional salience network to distractions. The theoretical and potentially clinical implications of these results are discussed, taking into account the specific scientific context of each study, the analytical tools used (event-related potentials, source location, microstates) and their limitations. In sum, our data suggest that mindfulness meditation may induce a reorganization of the cortico-subcortical loops that govern attentional behavior, and may be useful in the treatment of ADHD.
La neurofisiologia del movimento e dell’apprendimento motorio occupa un ampio campo scientifico. Le basi fondamentali dell’elaborazione centrale del movimento si inseriscono in strutture cerebrali molto specifiche sul piano anatomico e funzionale, ma anche riccamente interconnesse, formando insiemi neuronali gerarchici e dinamici. L’obiettivo principale di questo articolo è di introdurre le basi generali dell’apprendimento motorio, ottenute attraverso esperimenti a partire da modelli animali elementari, per integrarle progressivamente a comportamenti motori più complessi. Le basi delle oscillazioni neuronali e dell’apprendimento motorio, che coinvolgono il potenziamento e la depressione a lungo termine, e i meccanismi che risiedono nella membrana dei neuroni così come quelli che attivano il materiale genetico neuronale sono considerati nel loro contesto sperimentale iniziale, prima di essere descritti in comportamenti motori più complessi negli esseri umani. Si propone una visione aggiornata dei diversi sistemi corticali e subcorticali alla base della neurofisiologia del movimento e della sua plasticità. La struttura dinamica proposta incorpora le aree corticali coinvolte nell’organizzazione del movimento volontario e dell’orientamento sensoriale, così come il ruolo dei gangli della base e del cervelletto. Infine, la descrizione dei neuroni specchio e del modello interno dovrebbe permettere di capire meglio la dinamica generale dell’apprendimento del gesto motorio portato dall’attività oscillatoria del cervello.
La neurofisiología del movimiento y del aprendizaje motor abarca un campo científico muy amplio. Las bases fundamentales de la elaboración central del movimiento se inscriben en estructuras cerebrales muy específicas desde los puntos de vista anatómico y funcional, pero también profusamente interconectadas, formando conjuntos neuronales jerarquizados y dinámicos. El objetivo principal de este artículo consiste en presentar las bases generales del aprendizaje motor obtenidas a partir de los experimentos con modelos animales elementales, con el fin de integrarlas progresivamente en comportamientos motores más complejos. Antes de describirlos como parte de conductas motoras más complejas en seres humanos, se considerarán, en su entorno experimental inicial, las bases de las oscilaciones neuronales y del aprendizaje motor, que involucran la potenciación y la depresión a largo plazo, así como los mecanismos que se localizan en la membrana de las neuronas y los que activan el material genético neuronal. Se propone una visión actualizada de los diferentes sistemas corticales y subcorticales, que se encuentran en la base de la neurofisiología del movimiento y de su plasticidad. La estructura dinámica propuesta integra las áreas corticales implicadas en la organización del acto voluntario y de la orientación sensorial, así como el papel de los núcleos de la base y del cerebelo. Finalmente, la descripción de las neuronas espejo y del modelo interno debería permitir comprender mejor la dinámica general del aprendizaje del acto motor que sustenta la actividad oscilatoria del cerebro.
Peptidylarginine deiminases (PADs) are a group of posttranslational modification enzymes that citrullinate (deiminate) protein arginine residues in a calcium ion-dependent manner. Enzymatic citrullination abolishes the positive charges of native protein molecules, inevitably causing significant alterations in their structure and functions. Protein citrullination is important for the formation of the cornified layer of the skin that covers the human body. Despite this beneficial function, protein citrullination can also be detrimental as its accumulation in the brain is a possible cause of Alzheimer’s disease (AD). In this chapter, we introduce PADs and their protein citrullination function now considered critical for advancing research on aging and neurodegenerative disorders, especially AD.
Peptidylarginine deiminases (PADs) are a group of posttranslational modification enzymes that citrullinate (deiminate) protein arginine residues in a calcium ion-dependent manner. Enzymatic citrullination abolishes positive charges of native protein molecules, inevitably causing significant alterations in their structure and functions. Deiminated protein provides the important physiological advantage of forming a cornified layer of skin that covers the human body (see Chap. 7 for more details). Despite this beneficial function, deimination also has a negative side, because the accumulation of these proteins in the brain is a possible cause of Alzheimer's disease (AD). In this chapter, we introduce PADs and their protein citrullination function, which is now considered critical for advancing research on aging and neurodegenerative disorders, especially AD. © 2014 Springer Science+Business Media New York. All rights reserved.
Ethanol consumption during pregnancy is a major public health problem that causes persistent neurobehavioral deficits that significantly affect quality of life. In this review, we summarize the impact of developmental ethanol exposure on the central nervous system. We then discuss the developmental effects of ethanol on the hippocampus, a brain region involved in learning and memory, focusing on alterations in adult neurogenesis and synaptic plasticity. We also review studies on cerebellar synaptic transmission and plasticity. Finally, we address the impact of ethanol on reward pathways, with emphasis on potential mechanisms that could explain the higher incidence of alcohol and drug abuse in patients with Fetal Alcohol Spectrum Disorders. Potential interventions that could be useful in ameliorating the neurobehavioral effects of ethanol are discussed.
In the zebrafish (Danio rerio) olfactory epithelium, the calcium-binding proteins (CBPs) calretinin and S100/S100-like protein are mainly expressed in ciliated or crypt olfactory sensory neurons (OSNs), respectively. In contrast parvalbumin and calbindin1 have not been investigated. We present a combinatorial immunohistological analysis of all four CBPs, including their expression in OSNs and their axonal projections to the olfactory bulb in larval and adult zebrafish. A major expression of calretinin and S100 in ciliated and crypt cells, respectively, with some expression of S100 in microvillous cells is confirmed. Parvalbumin and calbindin1 are strongly expressed in ciliated and microvillous cells, but not in crypt cells. Moreover, detailed combinatorial double-label experiments indicate that there are eight subpopulations of zebrafish OSNs: S100-positive crypt cells (negative for all other three CBPs), parvalbumin only, S100 and parvalbumin, parvalbumin and calbindin1, and parvalbumin and calbindin1 and calretinin-positive microvillous OSNs, as well as a major parvalbumin and calbindin1 and calretinin, and minor parvalbumin and calbindin1 and calretinin-only-positive ciliated OSN populations. CBP-positive projections to olfactory bulb are consistent with previous reports of ciliated OSNs projecting to dorsal and ventromedial glomerular fields and microvillous OSNs to ventrolateral glomerular fields. We newly describe parvalbumin-positive fibers to the mediodorsal field which is calretinin free, with its anterior part showing additionally calbindin1-positive fibers, but absence thereof in the posterior part, indicating an origin from microvillous OSNs in both parts. One singular glomerulus (mdG2) exhibits S100 and parvalbumin-positive fibers, apparently originating from all crypt cells plus some microvillous OSNs. Arguments for various olfactory labeled lines are discussed.
The cerebellar cortex, the brain region responsible for motor coordination and learning expresses a high density of B-type γ-aminobutyric acid receptor (GABAbR). Previous in-vitro and in-situ studies indicated that cerebellar GABAbR may mediate multiple forms of inhibitory and excitatory modulation of cerebellar circuits. Nevertheless, the in-vivo influence of cerebellar GABAbR activation is unclear. As the first step in addressing this issue, we examined how pharmacological activation of cerebellar GABAbR modulates optokinetic reflex (OKR), an involuntary cerebellum-dependent eye movement for stabilizing the retinal image against the drift of the visual scene. We injected baclofen, a GABAbR-selective agonist, or control saline into the cerebellar flocculi of adult mice and then performed 1-hr OKR measurement sessions on two consecutive days. In the day 1 session, the baclofen (5 nM)-injected mice and control mice showed similar initial OKR gains and similar training-induced increases in the OKR gain (OKR adaptation). This result suggests that GABAbR activation does not affect cerebellar computation for executing OKR and formation of short-term memory for OKR adaptation. At the beginning of the day 2 session, the baclofen (5 nM or 50 μM)-injected mice showed an OKR gain higher than that achieved in the day 1 session while the control mice did not. This result suggests that GABAbR activation may facilitate the formation of OKR adaptation-related long-term memory. These findings provide a new insight into the functional architecture of the cerebellar circuits and indicate GABAbR to be a new target of pharmacological therapy against diseases with cerebellar dysfunction.
La neurofisiologia del movimento e dell’apprendimento motorio ricopre un campo scientifico molto vasto. Le basi fondamentali dell’elaborazione centrale del movimento si inscrivono in alcune strutture cerebrali molto specifiche sul piano anatomico e funzionale ma anche riccamente interconnesse, che formano degli insiemi neuronali gerarchizzati e dinamici. L’obiettivo principale di questo capitolo consiste nell’introdurre le basi generali dell’apprendimento motorio ottenute grazie alle esperienze realizzate a partire da modelli animali elementari, per integrarle gradualmente a comportamenti motori più complessi. Le basi dell’apprendimento neuronale che coinvolgono il potenziamento e la depressione a lungo termine e i meccanismi che hanno sede a livello della membrana dei neuroni, così come quelli che attivano il materiale genetico neuronale, sono considerati nel loro contesto sperimentale iniziale, prima di essere descritti all’interno di comportamenti motori più complessi che coinvolgono in particolare la motricità umana. È proposta una visione aggiornata dei differenti sistemi corticali e sottocorticali alla base della neurofisiologia del movimento e della sua plasticità. La struttura dinamica proposta integra le aree corticali implicate nell’organizzazione del gesto volontario e della guida sensoriale, così come il ruolo dei nuclei della base e del cervelletto. Infine, la descrizione dei neuroni specchio e del modello interno dovrebbe permettere di afferrare meglio la dinamica generale del gesto motorio e del suo apprendimento.
Senescence-accelerated mouse prone (SAMP) strains of mice show early onset of senescence, whereas senescence-accelerated mouse resistant (SAMR) strains are resistant to early senescence and serve as controls. Although SAMP6 and SAMP8 are established models of central nervous system alterations, it is unclear whether SAMP1/Sku (SAMP1) is characterized by brain alterations and dysfunction related to behavioral functioning. In the present study, behavioral tests (i.e., locomotor activity, Y-maze, rotating rod, hind-limb extension, and traction), histochemistry, and Western blot analyses were employed to study this mouse model using 2- and 4-month-old SAMP1 and age-matched control SAMR1. Although 2-month-old SAMP1 and SAMR1 showed similar activity, 4-month-old SAMP1 exhibited less activity than age-matched SAMR1 in locomotor activity and Y-maze tests. In rotating rod test, 2- and 4-month-old SAMP1 showed motor-coordination dysfunction. An abnormal extension reflex in the hind-limb test was observed in 2- and 4-month-old SAMP1. There were no significant differences between SAMP1 and SAMR1 with respect to grip strength in the traction test or alternation behavior in the Y-maze test. Histochemistry and Western blot analyses exhibited that cerebellar Purkinje cells in 4-month-old SAMP1 mice persistently expressed tyrosine hydroxylase. These results suggest that SAMP1 is a useful model for examining mechanisms underlying motor dysfunction.
The origin of the mammalian order Primates is nested within a Euarchontan ancestry that was probably exploiting the fine branch arboreal niche in a facultative way. A putative transition into this habitat may have begun with a more generalized small-bodied mammal that lacked climbing specializations for grasping hands and feet. Here, we investigate whether mice exhibit central nervous system (CNS) plasticity associated with learning to grasp/climb proficiently. House mice were used to study phenotypic plasticity within the cerebellum and primary somatosensory cortex associated with the fine branch niche. This experimental treatment has previously been shown to influence skeletal plasticity in part because climb-training encourages tail use and facultative pedal grasping. The CNS necessary to coordinate and control these locomotor behaviors was investigated in a standard mouse model (N = 10 male CD-1/ICR mice), and plasticity was detected by histomorphometric and immunohistologic changes within the cerebellum and cerebrum. The climbing group had a significantly smaller relative granule cell layer in cerebellar lobule 1-3 than the control group (P < 0.10), but increased nerve growth factor immunoreactivity in white matter tracts of these lobules (P < 0.05). Qualitative observations in the primary somatosensory cortex revealed greater pyramidal/stellate cell counts in climbers. We suggest that coordinated tail and hindlimb learning within the arboreal milieu is facilitated by increased growth factor expression and neuronal alterations in the CNS. These findings suggest that mammals with a generalized Euarchontogliran body plan were capable of facultative pedal grasping and tail use so as to exploit the terminal branch niche. Anat Rec, 2013. © 2013 Wiley Periodicals, Inc.
Synaptic plasticity, a cellular basis of learning and memory, has been studied extensively at excitatory synapses. Although synaptic plasticity has also been reported at inhibitory synapses, the molecular mechanism remains elusive. Here we attempted to clarify the overall signaling cascades regulating the induction of inhibitory synaptic plasticity in the cerebellum.
Rebound potentiation (RP), a long-lasting increase in GABA A receptor (GABA A R) responsiveness, is induced by postsynaptic depolarization of a Purkinje neuron (PN) at synapses formed with inhibitory interneurons (stellate or basket neurons). Previously, we showed that RP is suppressed by homosynaptic activation during depolarization through activation of the postsynaptic GABA B receptor (GABA B R). Activation of GABA B R reduces cAMP-dependent protein kinase (PKA) activity via the G i /G o -protein. Here we examined the molecular pathway through which PKA activity affects RP induction.
We confirmed that inhibition of Ca ²⁺ /calmodulin-dependent protein kinase II (CaMKII) or PKA suppresses RP. We also found that inhibition of protein phosphatase 1 (PP-1) or calcineurin (PP-2B) impaired suppression of RP induction. Inhibition of either PP-1 or calcineurin abolished RP impairment by PKA inhibition, but not that by CaMKII inhibition. Antisense oligonucleotide-mediated knock down of DARPP-32, which is a substrate of PKA and calcineurin and inhibits PP-1 when phosphorylated by PKA, suppressed RP. Furthermore, activation of GABA B R inhibited CaMKII activation through PKA inhibition and PP-1 activity. These results suggest that calcineurin activation accompanied by PKA inhibition in a PN causes dephosphorylation of DARPP-32, which releases PP-1 from inhibition. PP-1 in turn inhibits CaMKII activity, which is then directly involved in the RP induction.
The olivocerebellar system is known to generate periodic synchronous discharges that result in synchronous (to within 1 msec) climbing fiber activation of Purkinje cells (complex spikes) organized in parasagittally oriented strips. These results have been obtained primarily in anesthetized animals, and so the question remains whether the olivocerebellar system generates such patterns in the awake animal. To this end, multiple electrode recordings of crus 2a complex spike activity were obtained in awake rats conditioned to execute tongue movements in response to a tone. After removal of all movement- and tone-related activity, the remaining data were examined to characterize spontaneous complex spike activity in the alert animal. Spontaneous complex spikes occurred at an average firing rate of 1 Hz and a clear approximately 10 Hz rhythmicity. Analysis of the autocorrelograms using a rhythm index indicated that the large majority of Purkinje cells displayed rhythmicity, similar to that in the anesthetized preparation. In addition, the patterns of synchronous complex spike activity were also similar to those observed in the anesthetized preparation (i.e., simultaneous activity was found predominantly among Purkinje cells located within the same parasagittally oriented strip of cortex). The results provide unequivocal evidence that the olivocerebellar system is capable of generating periodic patterns of synchronous activity in the awake animal. These findings support the extrapolation of previous results obtained in the anesthetized preparation to the waking state and are consistent with the timing hypothesis concerning the role of the olivocerebellar system in motor coordination.
Many cortical structures have elevated firing rates during working memory, but it is not known how the activity is maintained. To investigate whether reverberating activity is important, we studied the temporal structure of local field potential (LFP) activity and spiking from area LIP in two awake macaques during a memory-saccade task. Using spectral analysis, we found spatially tuned elevated power in the gamma band (25−90 Hz) in LFP and spiking activity during the memory period. Spiking and LFP activity were also coherent in the gamma band but not at lower frequencies. Finally, we decoded LFP activity on a single-trial basis and found that LFP activity in parietal cortex discriminated between preferred and anti-preferred direction with approximately the same accuracy as the spike rate and predicted the time of a planned movement with better accuracy than the spike rate. This finding could accelerate the development of a cortical neural prosthesis.
Genomic imprinting is a process that determines differential expression of genes according to their parental origin. Most imprinted genes play roles in growth, development and tumour suppression. Angelman syndrome is one of the most studied human diseases related to a gene that is expressed on the maternal chromosome only (at least in certain brain cells). It is caused by inactivation of the UBE3A gene in the brain due to various abnormalities of chromosome 15q11-q13 inherited from the mother. Its phenotype includes developmental delay, absent speech, motor impairment, a typical electroencephalogram, seizures and a peculiar behaviour. Lack of UBE3A expression may result from deletion of the 15q11-q13 region where this gene and GABRB3 are located, paternal uniparental disomy, imprinting defect or UBE3A mutation. Animal models corresponding to the different molecular classes have been generated. An integrative hypothesis for the molecular pathophysiology of the syndrome suggests dysregulation of synaptic neurotransmission through UBE3A-related modulation of functional GABA A receptors and GABRB3-related amount of β3 sub-unit in these receptors. This would account for developmental changes as well as for the differences in severity between deletion and non-deletion cases. In addition to rehabilitation programmes adapted to the patients' individual needs, promising management approaches may include pharmacological agents interfering with GABA A receptors, increasing GABRB3 expression or altering DNA methylation.
The implications for motor learning of the model developed in the previous article are analyzed using idealized Pavlovian eyelid conditioning trials, a simple example of cerebellar motor learning. Results suggest that changes in gr-->Pkj synapses produced by a training trial disrupt equilibrium and lead to subsequent changes in the opposite direction that restore equilibrium. We show that these opposing phases would make the net plasticity at each gr-->Pkj synapse proportional to the change in its activity during the training trial, as influenced by a factor that precludes plasticity when changes in activity are inconsistent. This yields an expression for the component of granule cell activity that supports learning, the across-trials consistency vector, the square of which determines the expected rate of learning. These results suggest that the equilibrium maintained by the cerebellar-olivary system must be disrupted in a specific and systematic manner to promote cerebellar-mediated motor learning.
Earlier efforts to localize the symptoms of schizophrenia in a single brain region have been replaced by models that postulate
a disruption in parallel distributed or dynamic circuits. Based on empirical data derived from both magnetic resonance and
positron emission tomography, we have developed a model that implicates connectivity among nodes located in prefrontal regions,
the thalamic nuclei, and the cerebellum. A disruption in this circuitry produces “cognitive dysmetria,” difficulty in prioritizing,
processing, coordinating, and responding to information. This “poor mental coordination” is a fundamental cognitive deficit
in schizophrenia and can account for its broad diversity of symptoms.
Pyramidal cells in the CA1 hippocampal region displayed transient network oscillations (200 hertz) during behavioral immobility, consummatory behaviors, and slow-wave sleep. Simultaneous, multisite recordings revealed temporal and spatial coherence of neuronal activity during population oscillations. Participating pyramidal cells discharged at a rate lower than the frequency of the population oscillation, and their action potentials were phase locked to the negative phase of the simultaneously recorded oscillatory field potentials. In contrast, interneurons discharged at population frequency during the field oscillations. Thus, synchronous output of cooperating CA1 pyramidal cells may serve to induce synaptic enhancement in target structures of the hippocampus.
This study was intended to test the adaptive plasticity of the vestibulo-ocular reflex before and after either a midsagittal or parasagittal incision in the brainstem. Eye movements were measured with the electromagnetic search coil technique during the vestibulo-ocular reflex (VORD) in the dark, the optokinetic reflex (OKN), and the visuo-vestibular adaptive training procedure. Two types of visual-vestibular combined stimulation were applied by means of low frequency stimuli (0.05 to 0.10 Hz). In order to increase or decrease the VORD gain, the optokinetic drum was oscillated either 180 ° out-of-phase or in-phase with the vestibular stimulus turntable. This "training" procedure was applied for 4 hours. Initial measurements of the VORD were normal with a mean gain value of 0.92 ± 0.08. After 4 hours of "training" with the out-of-phase condition (180 °), VORD gain reached mean values of 1.33 ± 0.11 (n = 6 cats). In the in-phase combination, the mean VORD gain decreased from 1.0 to 0.63 ± 0.02 (n = 2 cats). No significant change of VORD phase was found in any of the cats. Midsagittal or parasagittal pontomedullary brainstem incisions were performed in 4 cats. Recovery of the VOR was tested on the 2nd, 7th, and 30th day after operation. After the 30th day, recovery of the VORD gain stabilized at about 66% of the initial preoperative value. At this stage of the recovery, the optokinetic response (OKN) of the midsagittal-lesioned cats was practically normal: in the parasagittal-lesioned cats, the postoperative OKN responses were asymmetric. After stabilization of recovery, lesioned cats were trained with the same adaptation procedure. Although the direct effect of the visuo-vestibular combined stimulation during the training was still operative in all lesioned cats, the adaptive plasticity was completely abolished by the lesions. These results suggest that the commissural brainstem network may play a crucial role in the acquisition of the forced VOR adaptation.
This article reviews the electroresponsive properties of single neurons in the mammalian central nervous system (CNS). In
some of these cells the ionic conductances responsible for their excitability also endow them with autorhythmic electrical
oscillatory properties. Chemical or electrical synaptic contacts between these neurons often result in network oscillations.
In such networks, autorhythmic neurons may act as true oscillators (as pacemakers) or as resonators (responding preferentially
to certain firing frequencies). Oscillations and resonance in the CNS are proposed to have diverse functional roles, such
as (i) determining global functional states (for example, sleep-wakefulness or attention), (ii) timing in motor coordination,
and (iii) specifying connectivity during development. Also, oscillation, especially in the thalamo-cortical circuits, may
be related to certain neurological and psychiatric disorders. This review proposes that the autorhythmic electrical properties
of central neurons and their connectivity form the basis for an intrinsic functional coordinate system that provides internal
context to sensory input.
Responses evoked in Purkinje cells by climbing fibre activity were investigated by recording from Purkinje cell axons in the cerebellum of anaesthetized cats. Purkinje cell axons were identified by firing pattern and by latency of responses to stimulation of peripheral nerve and of the inferior olive. Axonal climbing fibre responses usually consisted of one to two spikes, suggesting that normally only the initial spike or, at most, this and one of the secondary spikes are propagated down the Purkinje cell axon. When two successive climbing fibre responses were evoked, the number of spikes in the second response was increased, usually up to three to five. This effect could be obtained at stimulation intervals of up to 100 ms. In a few cases it was possible for a climbing fibre response to be preceded by a parallel fibre volley evoked by stimulation of the cerebellar surface. This increased the number of spikes in the axonal climbing fibre response. The results suggest that the number of propagated spikes in the climbing fibre response can be modified by a preceding input to the Purkinje cell.
We recorded multiunit neural activity in the granule cell layer of cerebellar folium Crus IIa in unrestrained rats. Seven- to 8-Hz oscillatory activity was seen during behavioral states in which the animal was immobile; any movement the animal made coincided with termination of the oscillations. However, nearly one-third of oscillatory episodes appeared to cease spontaneously, in the absence of any observable sensory input or movement. Oscillations were synchronized both within and between cerebellar hemispheres, demonstrating precise temporal coordination among multiple, bilateral levels of the somatosensory system. We interpret these data in the context of similar oscillations observed in other brain structures and suggest that the oscillations are an underlying dynamic property of the entire somatosensory network.
We provide physiological, pharmacological, and structural evidence that axons of hippocampal principal cells are electrically coupled, with prepotentials or spikelets forming the physiological substrate of electrical coupling as observed in cell somata. Antidromic activation of neighboring axons induced somatic spikelet potentials in neurons of CA3, CA1, and dentate gyrus areas of rat hippocampal slices. Somatic invasion by these spikelets was dependent on the activation of fast Na(+) channels in the postjunctional neuron. Antidromically elicited spikelets were suppressed by gap junction blockers and low intracellular pH. Paired axo-somatic and somato-dendritic recordings revealed that the coupling potentials appeared in the axon before invading the soma and the dendrite. Using confocal laser scanning microscopy we found that putative axons of principal cells were dye coupled. Our data thus suggest that hippocampal neurons are coupled by axo-axonal junctions, providing a novel mechanism for very fast electrical communication
The cerebellum consists of anatomically and functionally independent units. The cortical component of the unit is a narrow sagittal zone that has a width of about one mm in the cat and extends throughout several lobules, sometimes throughout the entire cerebellum. Along the unfolded cortex, the length would be tens or hundreds of mm in the cat. The sagittal zones are oriented orthogonally to the folia and have, therefore, like the folia, a fixed relation to the geometrical pattern formed by the neuronal elements in the cerebellar cortex. Each sagittal zone receives climbing fibres from a circumscribed region of the inferior olive. The axon from an olivary neuron usually divides only in the sagittal plane to supply climbing fibres to a few Purkinje cells within the same zone. Each sagittal zone sends its Purkinje cell axons to a particular efferent (cerebellar or vestibular) nucleus, which also receives collaterals from the climbing fibres projecting to that zone.
Vertebrate cerebella occupy a position in the rostral roof of the 4th ventricle and share a common pattern in the structure of their cortex. They differ greatly in their external form, the disposition of the neurones of the cerebellar cortex and in the prominence of their afferent, intrinsic and efferent connections.
It is generally believed that a smooth execution of a compound movement, or motor coordination, requires learning of component movements as well as experience-based refinement of the motor program as a whole. PKCγ mutant mice display impaired motor coordination but intact eyeblink conditioning, a form of component movement learning. Cerebellar long-term depression, a putative cellular mechanism for component motor learning, is also unimpaired. Thus, PKCγ mutant mice are defective in refinement of the motor program. In the accompanying paper, we demonstrate that innervation of multiple climbing fibers onto Purkinje cells persists in adulthood in these mutant mice. We propose that this defective elimination of surplus climbing fibers underlies motor discoordination.
The functional units of the cerebellar cortex have been identified as sagittal zones with a width of about 1 mm and a length of up to more than 100 mm. These zones can be divided into sagittal microzones with a width of 200 μm or less. The microzones and their efferent relay neurones in the cerebellar nuclei might form the operational units of the cerebellum, corresponding in a sense with the classical cell columns of the cerebral cortex.
We used positron emission tomography (PET) to study brain [11C]flumazenil (FMZ) binding in four Angelman syndrome (AS) patients. Patients 1 to 3 had a maternal deletion of 15q11-q13 leading to the loss of β3 subunit of γ-aminobutyric acidA/benzodiazepine (GABAA/BZ) receptor, whereas Patient 4 had a mutation in the ubiquitin protein ligase (UBE3A) saving the β3 subunit gene. [11C]FMZ binding potential in the frontal, parietal, hippocampal, and cerebellar regions was significantly lower in Patients 1 to 3 than in Patient 4. We propose that the 15q11-q13 deletion leads to a reduced number of GABAA/BZ receptors, which could partly explain the neurological deficits of the AS patients. Ann Neurol 2001;49:110–113
Three unrelated children are described with similar physical abnormalities of congenital origin, reminiscent of puppet children, and profound mental retardation.
Enfants ‘marionnettes’
L'auteur decrit trois enfants atteints d'anomalies physiques similaires d'origine congénitale et d'un retard mental profond.
‘Puppenkinder’
Drei Kinder werden beschrieben, mit einander gleichenden physischen Abnormitäten kongenitalen Ursprungs sowie schwerwiegender geistiger Zurückgebliebenheit.
Niños ‘muñecos’
Se describen tres niños con anormalidades fisicas parecidas, de origen congénita, además de atraso mental profundo.
Protein kinase C (PCK) is a family of isoforms that are implicated in subcellular signal transduction. The authors investigated the distribution of several PKC isoforms (PKC-α, PKC-β, PKC-γ, PKC-δ, and PKC-ϵ) within major cerebellar cell types as well as cerebellar projection target neurons, including Purkinje neurons, cerebellar nuclear neurons, and secondary vestibular neurons. PKC-α, PKC-β, PKC-γ, PKC-δ, and PKC-ϵ are found within the cerebellum. Of these isoforms, PKC-γ and PKC-δ are highly expressed in Purkinje cells. PKC-γ is expressed in all Purkinje cells, whereas the expression of PKC-δ is restricted to sagittal bands of Purkinje cells in the posterior cerebellar cortex. In the lower folia of the uvula and nodulus, Purkinje cell expression of PKC-δ is uniformly high, and the sagittal banding for PKC-δ expression is absent. Within the cerebellar nuclei, PKC-δ-immunolabeled axons terminate within the medial aspect of the caudal half of the ipsilateral interpositus nucleus. PKC δ-immunolabeled axons also terminated within the caudal medial and descending vestibular nuclei (MVN and DVN, respectively), the parasolitary nucleus (Psol), and the nucleus prepositus hypoglossi (NPH). PKC-γ-immunolabeled axons terminated in all of the cerebellar nuclei as well as in the lateral and superior vestibular nuclei and the MVN, DVN, Psol, and NPH. The projection patterns of PKC-immunolabeled Purkinje cells were confirmed by lesion-depletion studies in which unilateral uvula-nodular lesions caused depletion of PKC-immunolabeled terminals ipsilateral to the lesion in the vestibular complex. These data identify circuitry that is unique to cerebellar-vestibular interactions. J. Comp. Neurol. 427:235–254, 2000. © 2000 Wiley-Liss, Inc.
Direct cell-to-cell communication through specialized intercellular channels is a characteristic feature of virtually all multi-cellular organisms. The remarkable functional conservation of cell-to-cell coupling throughout the animal kingdom, however, is not matched at the molecular level of the structural protein components, Thus protostomes (including nematodes and flies) and deuterostomes (including all vertebrates) utilize two unrelated families of gap-junction genes, innexins and connexins, respectively. The recent discovery that pannexins, a novel group of proteins expressed by several organisms, are able to form intercellular channels has started a quest to understand their evolutionary relationship and functional contribution to cell communication in vivo. There are three pannexin genes in mammals, two of which are co-expressed in the developing and adult brain. Of note, pannexin1 can also form Ca2+, activated hemichannels that open at physiological extracellular Ca2+ concentrations and exhibit distinct pharmacological properties.
The adult olivocerebellar axons and their terminal arbours, the climbing fibres, are capable of remarkable structural plasticity, regulated through their interaction with Purkinje cells. When these cells are deleted, terminal climbing fibre branches retract. In contrast, there is a vigorous outgrowth of entire terminal arbours when extra postsynaptic neurones are available. The new connections lead to a functional, highly specific pattern of innervation at the single Purkinje cell level and are topographically organized according to the principles of the original projection map. A reversible climbing fibre retraction occurs following depression of electrical activity of the cerebellar cortex. These remarkable plastic properties, together with the fact that these neurones express several growth-associated genes constitutively, suggest that the climbing fibre synapses might be adjusted dynamically to participate in physiological plasticity.
Racemic ketamine HCl, its optical isomers and the metabolites of the parent drug were incubated with synaptosomal-rich fractions obtained from rat cerebral cortex to evaluate the effect of these agents on the high affinity transport processes of the monoamine neurotransmitters. Each of the agents caused a concentration-dependent inhibition of the transport processes. The (+) isomer of ketamine HCl was about four times more potent than the (−) isomer on catecholamine transport while the (−) isomer appeared slightly more effective against serotonin transport. Both metabolite I and II of ketamine were weaker inhibitors than the parent drug. Metabolite I was shown to be a competitive inhibitor as had previously been demonstrated for ketamine, and was also found to inhibit the oxidative deamination of the monoamines more effectively than ketamine. The possible significance of the effects of the optical isomers and the metabolites of ketamine on monoamine metabolism is discussed in relation to quantitative differences observed in the pharmacological activity of the agents.
The cerebellum plays an essential role in motor control, and its dysfunction may delay the onset of action and disrupt smooth and efficient movement. A Purkinje neuron (PN), the sole output cell type in the cerebellar cortex, receives two distinct types of excitatory synaptic inputs, numerous weak inputs from granule neurons (GNs) and occasional strong inputs from a climbing fiber (CF). The role of each input and the significance of low firing rate of CF have been studied. Here we show that the increased occurrence of CF inputs altered the firing pattern of a PN, which was correlated with timing of a reflex. We used the mutant mice deficient in the glutamate receptor delta2 subunit, a molecule related to ionotropic glutamate receptor specifically expressed at GN-PN synapses. The mutant mouse shows more frequent CF inputs and longer timing delay in optokinetic response (OKR), reflex eye movement that follows slow motion of a large visual field. A PN shows two types of action potentials: complex spikes (CS) induced by CF inputs; and simple spikes. They changed respective firing rates during sinusoidal optokinetic stimulation, and the timing of each firing rate modulation was similar in wild-type and mutant mice. However, increased occurrence of CS in the mutant altered the total firing pattern of a PN in the flocculus, which was correlated with the timing delay of OKR. These results support the functional merit of low firing rate of CF in motor control.
The most important function of the cerebellum may be to coordinate motor function so that movements can be performed smoothly, but there are others. It has been shown that the cerebellum is involved in certain aspects of cognition and changes in affect. Also verbal deficits can be found after cerebellar lesions. The cerebellar cognitive affective syndrome is described, and the evidence for its existence discussed; in particular the use of neuroimaging studies. Different areas of the cerebellum have been identified as serving the various functions, and also their connections to the relevant parts of the cerebral cortex. Certain conditions merit special attention. The function of spatial navigation needs a major contribution from the cerebellum, and the problems of autism and impaired cognition are no doubt related to the enlarged cerebellum described in this disorder. The cognitive defects found in children with cerebellar ataxia supports its role in learning, and so does the study of music.
Cerebellar parallel fiber (PF)-Purkinje cell (PC) synapses can undergo postsynaptically expressed long-term depression (LTD) or long-term potentiation (LTP) depending on whether or not the climbing fiber (CF) input is coactivated during tetanization. Here, we show that modifications of the postsynaptic calcium load using the calcium chelator BAPTA or photolytic calcium uncaging result in a reversal of the expected polarity of synaptic gain change. At higher concentrations, BAPTA blocks PF-LTP. These data indicate that PF-LTD requires a higher calcium threshold amplitude than PF-LTP induction and suggest that CF activity acts as a polarity switch by providing dendritic calcium transients. Moreover, previous CF-LTD induction changes the relative PF-LTD versus -LTP induction probability. These findings suggest that bidirectional cerebellar learning is governed by a calcium threshold rule operating "inverse" to the mechanism previously described at other glutamatergic synapses (BCM rule) and that the LTD/LTP induction probability is under heterosynaptic climbing fiber control.
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Vertebrate cerebella occupy a position in the rostral roof of the 4th ventricle and share a common pattern in the structure of their cortex. They differ greatly in their external form, the disposition of the neurons of the cerebellar cortex and in the prominence of their afferent, intrinsic and efferent connections.
The cerebellar molecular layer in adult rats has been studied with the electron microscope at several early and consecutive survival times following 3-acetylpyridine intoxication. Climbing fiber (CF) terminals underwent a fast process of electron-dense degeneration which became apparent from 16 hours onwards. A small proportion of degenerating terminals were depleted of vesicles and filled with a dark flocculent and granular homogeneous matrix. Microtubular changes in degenerating CF tendrils were observed. CF terminals were found in relation with every Purkinje cell in normal animals and completely disappeared within 72 hours after the treatment. CF synapses were found on Purkinje dendritic and somatic thorns, sometimes also on the dendritic shafts or even on the Purkinje soma. Convincing evidencd of synaptic contacts of CF varicosities on either basket or stellate cells could not be obtained. CF synapses with Golgi II cell dendrites in the molecular layer were described. Decrease in the number of post-synaptic dendritic thorns normally assigned for CF synapses was observed consequential to CF anterograde degeneration. The observations are consistent with previous conclusions drawn from light microscopic studies that the clearing up of CF debris in the molecular layer is completed within the short time of three days, and that the inferior olive seems to be the only source of CFs.
The pharmacological and single-channel properties of Ca2+ channels were studied in the somata and dendrites of adult cerebellar Purkinje cells. The Ca2+ channels were exclusively of the high threshold type: low threshold Ca2+ channels were not found. These high threshold channels were not blocked by omega-conotoxin GVIA and were inhibited rather than activated by BAY K 8644. They were therefore pharmacologically distinct from high threshold N- and L-type channels. Funnel web spider toxin was an effective blocker. The channels opened to conductance levels of 9, 14, and 19 pS (in 110 mM Ba2+). These slope conductances were in the range of those reported for N- and L-type channels. Our results are in agreement with previous reports suggesting that Ca2+ channels in Purkinje cells can be classified as P-type channels according to their pharmacology. The results also suggest that distinctions among Ca2+ channel types based on the single-channel conductance are not definitive.
Persistent changes in synaptic efficacy are thought to underlie the formation of learning and memory in the brain. High-frequency activation of an afferent excitatory fibre system can induce long-term potentiation, and conjunctive activation of two distinct excitatory synaptic inputs to the cerebellar Purkinje cells can lead to long-term depression of the synaptic activity of one of the inputs. Here we report a new form of neural plasticity in which activation of an excitatory synaptic input can induce a potentiation of inhibitory synaptic signals to the same cell. In cerebellar Purkinje cells stimulation of the excitatory climbing fibre synapses is followed by a long-lasting (up to 75 min) potentiation of gamma-aminobutyric acid A (GABAA) receptor-mediated inhibitory postsynaptic currents (i.p.s.cs), a phenomenon that we term rebound potentiation. Using whole-cell patch-clamp recordings in combination with fluorometric video imaging of intracellular calcium ion concentration, we find that a climbing fibre-induced transient increase in postsynaptic calcium concentration triggers the induction of rebound potentiation. Because the response of Purkinje cells to bath-applied exogenous GABA is also potentiated after climbing fibre-stimulation with a time course similar to that of the rebound potentiation of i.p.s.cs, we conclude that the potentiation is caused by a calcium-dependent upregulation of postsynaptic GABAA receptor function. We propose that rebound potentiation is a mechanism by which in vivo block of climbing fibre activity induces an increase in excitability in Purkinje cells. Moreover, rebound potentiation of i.p.s.cs is a cellular mechanism which, in addition to the long-term depression of parallel fibre synaptic activity, may have an important role for motor learning in the cerebellum.
Based on a review of cerebellar anatomy, neural discharge in relation to behavior, and focal ablation syndromes, we propose a model of cerebellar function that we believe is both comprehensive as to the available information (at these levels) and unique in several respects. The unique features are the inclusion of new information on (a) cerebellar output--its replicative representation of body maps in each of the deep nuclei, each coding a different type and context of movement, and each appearing to control movement of multiple body parts more than of single body parts; and (b) the newly assessed long length of the parallel fiber. The parallel fiber, by virtue of its connection through Purkinje cells to the deep nuclei, appears optimally designed to combine the actions at several joints and to link the modes of adjacent nuclei into more complex coordinated acts. We review the old question of whether the cerebellum is responsible for the coordination of body parts as opposed to the tuning of downstream executive centers, and conclude that it is both, through mechanisms that have been described in the cerebellar cortex. We argue that such a mechanism would require an adaptive capacity, and support the evidence and interpretation that it has one. We point out that many parts of the motor system may be involved in different types of motor learning for different purposes, and that the presence of the many does not exclude an existence of the one in the cerebellar cortex. The adaptive role of the cerebellar cortex would appear to be specialized for combining simpler elements of movement into more complex synergies, and also in enabling simple, stereotyped reflex apparatus to respond differently, specifically, and appropriately under different task conditions. Speed of learning and magnitude of memory for both novel synergies and task-specific performance modifications are other attributes of the cerebellar cortex.
Calretinin is a calcium-binding protein related to calbindin-D28k; both are present in different though overlapping sets of neurons in brains of birds and mammals. We describe in detail the pattern of calretinin immunoreactivity in the rat brain. As in chick brain, calretinin immunoreactivity is abundant in various sensory pathways (particularly certain cells and fibres of the cochlear nuclei and olfactory bulb), in the heterogeneous parts of the brainstem and in parts of the hypothalamus. Many primary sensory fibres are strongly positive. Major groups of calretinin-positive neurons also include the thalamic reticular nucleus, triangular septal nucleus, lateral mammillary nucleus and substantia nigra pars compacta. Many other calretinin-positive cells are recognizable as local inhibitory neurons. Calretinin is absent from all but a few cells in the cerebral cortex, and is never found in motor neurons. There are also some distinctive positive structures whose identity is uncertain, notably irregular "shells" of cells and fibres around the thalamus and in the amygdala and an unnamed cell type in the vestibulocerebellum.
LTD has now been established as a synaptic plasticity specific to the cerebellum. Cellular and molecular mechanisms of LTD have been elucidated to some extent, but still a number of questions are left open. The most crucial question may concern its time course, as to how long the LTD lasts beyond the limit of the present maximum observation time of 3 hr, and whether and how it is eventually transformed to a permanent memory. Molecular mechanisms underlying LTD should be investigated further in respect to Ca2+ binding and storage, protein kinase C, phosphorylation of glutamate receptors, GTP proteins, etc. The ineffectiveness of mass field potentials in representing LTD makes such studies relatively difficult, and a hope for future development may be placed in reproduction of LTD in tissue cultured Purkinje cells or even in isolated glutamate receptors in a simplified form. The cerebellar neuronal network incorporating LTD as a memory element has been conceived as a simple perceptron-like (Albus 1971) or adaptive filter-like (Fujita 1982a) parallel processing computer. Such a neuronal computer incorporated in a reflex or a more complex movement system would endow the system with subtle capabilities of adaptation and learning. The scheme of the floccular control of the VOR closely resembles that of a self-tuning regulator, a type of adaptive control system. For cerebellar control of voluntary movements, however, another version of the adaptive control system, the model reference control system, seems to be more applicable (Ito 1986). This system continuously readjusts its dynamics by referring to errors derived through comparison of its performance with that of an internal model. It is important to note that a model for an unknown system can be built based on the same principle, by feeding errors derived from their comparison to adjust the model. It may thus be conceived that an internal model is built within the cerebellum in the manner of model reference adaptive control, and that an internal model so formed is utilized for adaptive control of movement. A recent simulation study successfully reproduced learning in formation of an arm trajectory based on these principles of model reference control (Kawato et al 1987). On the experimental side, however, the complex neural organization for control of locomotion, posture, and voluntary movements still eludes full elucidation. Nevertheless, evidence is accumulating to support the cerebellar learning hypothesis.(ABSTRACT TRUNCATED AT 400 WORDS)
The diagnostic criteria for Fetal Alcohol Syndrome (FAS) are reviewed and the authors suggest a new diagnostic schema to allow for a more adequate description of the range of FAS. FAS is also reviewed by topic area. Associated problems believed to be caused by maternal alcohol ingestion are discussed.
Extracellularly recorded climbing fibre responses in Purkinje cell somata in the cerebellar cortex were investigated in cats deeply anaesthetized with barbiturate. The effects on the amplitude of initial and secondary spikes of preceding climbing fibre activation, on-beam parallel fibre activation and off-beam parallel fibre activation were studied. When a climbing fibre response was preceded by climbing fibre activation there was a decrease in the amplitude of the initial spike of the second response at intervals up to 25 ms and little effect at longer intervals. Secondary spike amplitude was greatly increased at intervals up to 100 ms. When a complex spike was preceded by on-beam parallel fibre activation there was a decrease in the initial spike amplitude at short intervals and an increase in the amplitude at long intervals. Secondary spike amplitude was increased up to 150 ms after an on-beam parallel fibre volley. When a complex spike was preceded by off-beam parallel fibre stimulation there was an increase in initial spike amplitude at intervals up to about 200 ms and a decrease in secondary spike amplitude at intervals up to about 150 ms. The results show that the amplitude of the secondary spikes can be modified by a preceding input to the Purkinje cell. The results also suggest that the secondary spikes are generated in the Purkinje cell dendrites and the initial spike in the soma.