FIGURE 9 - uploaded by Michael E Dailey
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Low magnification image of calbindin and PSD- 95 image of cerebellar cortex showing the distribution of postsynaptic sites of afferent mossy and climbing fibers in the granular layer (red hotspots), and the small puncta in the inner third molecular layer (small red puncta). The Purkinje cell bodies appear surrounded by the pericellular nest formed by basket cell axons (yellow).
Source publication
The localization of GluR1 subunits of ionotropic glutamate receptors in the glial cells and inhibitory neurons of cerebellar cortex and their association with the climbing and parallel fibers, and basket cell axons were studied. Samples of P14 and P21 rat cerebellar cortex were exposed to a specific antibody against GluR1 subunit(s) ofAMPA receptor...
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Objectives
This study aimed to investigate the impact of valproic acid (VPA) on the histone acetylation of acetaldehyde dehydrogenase 1A1 (ALDH1A1) and the mechanism underlying VPA-induced autism-like behavior.
Methods
Female Sprague-Dawley rats were intraperitoneally injected with VPA during gestation to establish an autism model in their offspri...
Citations
... Disruption of AMPA receptor trafficking by Abeta oligomers in the hippocampus is believed to be a major contributor to synaptic dysfunction in AD, leading to cognitive deficits 88 . Purkinje cells express all four AMPA receptor subunits GluA1-4 89,90 , and intense GluR1 immunoreactivity and mRNA expression are detected in the Purkinje cells 91,92 . We therefore speculate that synaptic dysfunction associated with downregulation of cerebellar Gria1 in ataxia mice and patients with ataxic manifestations, leading to motor deficits after PNI. ...
... Disruption of AMPA receptor trafficking by Abeta oligomers in the hippocampus is believed to be a major contributor to synaptic dysfunction in AD, leading to cognitive deficits 88 . Purkinje cells express all four AMPA receptor subunits GluA1-4 89,90 , and intense GluR1 immunoreactivity and mRNA expression are detected in the Purkinje cells 91,92 . We therefore speculate that synaptic dysfunction associated with downregulation of cerebellar Gria1 in ataxia mice and patients with ataxic manifestations, leading to motor deficits after PNI. ...
Peripheral nerve injury (PNI) often results in spontaneous motor recovery; however, how disrupted cerebellar circuitry affects PNI-associated motor recovery is unknown. Here, we demonstrated disrupted cerebellar circuitry and poor motor recovery in ataxia mice after PNI. This effect was mimicked by deep cerebellar nuclei (DCN) lesion, but not by damaging non-motor area hippocampus. By restoring cerebellar circuitry through DCN stimulation, and reversal of neurotransmitter imbalance using baclofen, ataxia mice achieve full motor recovery after PNI. Mechanistically, elevated glutamate-glutamine level was detected in DCN of ataxia mice by magnetic resonance spectroscopy. Transcriptomic study revealed that Gria1, an ionotropic glutamate receptor, was upregulated in DCN of control mice but failed to be upregulated in ataxia mice after sciatic nerve crush. AAV-mediated overexpression of Gria1 in DCN rescued motor deficits of ataxia mice after PNI. Finally, we found a correlative decrease in human GRIA1 mRNA expression in the cerebellum of patients with ataxia-telangiectasia and spinocerebellar ataxia type 6 patient iPSC-derived Purkinje cells, pointing to the clinical relevance of glutamatergic system. By conducting a large-scale analysis of 9,655,320 patients with ataxia, they failed to recover from carpal tunnel decompression surgery and tibial neuropathy, while aged-match non-ataxia patients fully recovered. Our results provide insight into cerebellar disorders and motor deficits after PNI.
... GluR1, a subunit of the AMPA subtype of glutamate receptor, is expressed in the cerebellum in inhibitory cerebellar neurons, at synapses associated with excitatory glutamatergic parallel fiber and climbing synapses, at inhibitory basket cell axons and in Bergman glial cells (Baude et al., 1994;Castejon and Dailey, 2009;Martin et al., 1993). GluR1 levels in cerebellum of alcohol naïve IL-6 tg mice were significantly reduced compared to GluR1 levels in cerebellum of alcohol naïve non-tg mice (U = 4, n 1 = 11, n 2 = 12, p = 0.0001, Mann-Whitney) (Fig. 3A1). ...
Recent studies indicate that neuroimmune factors, including the cytokine interleukin-6 (IL-6), play a role in the CNS actions of alcohol. The cerebellum is a sensitive target of alcohol, but few studies have examined a potential role for neuroimmune factors in the actions of alcohol on this brain region. A number of studies have shown that synaptic transmission, and in particular inhibitory synaptic transmission, is an important cerebellar target of alcohol. IL-6 also alters synaptic transmission, although it is unknown if IL-6 targets are also targets of alcohol. This is an important issue because alcohol induces glial production of IL-6, which could then covertly influence the actions of alcohol. The persistent cerebellar effects of both IL-6 and alcohol typically involve chronic exposure and, presumably, altered gene and protein expression. Thus, in the current studies we tested the possibility that proteins involved in inhibitory and excitatory synaptic transmission in the cerebellum are common targets of alcohol and IL-6. We used transgenic mice that express elevated levels of astrocyte produced IL-6 to model persistently elevated expression of IL-6, as would occur in alcohol use disorders, and a chronic intermittent alcohol exposure/withdrawal paradigm (CIE/withdrawal) that is known to produce alcohol dependence. Multiple cerebellar synaptic proteins were assessed by Western blot. Results show that IL-6 and CIE/withdrawal have both unique and common actions that affect synaptic protein expression. These common targets could provide sites for IL-6/alcohol exposure/withdrawal interactions and play an important role in cerebellar symptoms of alcohol use such as ataxia.
... The advent of electron microscopy and the freeze etching technique made possible to visualize spine morphology and its intramembrane morphology [1][2][3][4][5][6]. The development of confocal laser scanning microscopy and the immunohistochemistry techniques [7] allowed us to study the domains of mayor proteins inside the postsynaptic region of Purkinje dendritic spines [8][9][10]. ...
Correlative microscopy of cerebellar molecular layer allowed us to image the localization of postsynaptic receptors using a comparative and intermicroscopy study applying transmission electron microscopy (TEM), freeze-etching and direct replicas for transmission electron microscopy (FFTEM), field emission scanning electron microscopy (FESEM), and confocal laser scanning microscopy (CLSM) using immunohistochemistry of Synapsin-I and PSD-95, immunohistochemistry of Ca 2+ /calmodulin dependent protein kinase II alpha and immunohistochemistry GluR1 subunits of AMPA receptors alpha. These techniques showed the images of postsynaptic densities of parallel fibers-Purkinje dendritic ramifications containing postsynaptic proteins and glutamate postsynaptic receptors. The freeze-etching replica method for TEM showed the three-dimensional structure and intramembrane morphology of postsynaptic ellipsoidal and spheroid intramembrane particles. Confocal laser scanning microscopy using Synapsin-I (Syn-I) and PSD-95, GluR1 subunits of ionotropic glutamate receptors, and Ca 2+ /calmodulin dependent protein kinase II alpha contribute to image the precise localization of postsynaptic receptors. The high resolution FESEM showed 25-50nm globular subunits at the spine postsynaptic density corresponding to the localization of postsynaptic proteins and/or postsynaptic glutamate receptors.
... The advent of electron microscopy and the freeze etching technique made possible to visualize spine morphology and its intramembrane morphology [1][2][3][4][5][6]. The development of confocal laser scanning microscopy and the immunohistochemistry techniques [7] allowed us to study the domains of mayor proteins inside the postsynaptic region of Purkinje dendritic spines [8][9][10]. ...
... Recent studies reported strong immunoreactivity of GluR1/AMPA receptor subunit in P14 and P21 Wistar rat cerebellar cortex, and described that propofol slowed the channel kinetics of the AMPA receptor by elevating phosphorylation in GluR1. [16][17][18] We hypothesize that the slowing in decay time of PF-EPSC could be related to cerebellar dysfunction caused by propofol. Slowing of the EPSC decay may contribute to slower rising EPSPs and increased duration of the EPSP plateau, and should also worsen the temporal precision of spike generation, which will block fine motor control in the cerebellar circuits. ...
Objective
Propofol is an intravenously administered anesthetic that enhances γ-aminobutyric acid-mediated inhibition in the central nerve system. Other mechanisms may also be involved in general anesthesia. Propofol has been implicated in movement disorders. The cerebellum is important for motor coordination and motor learning. The aim of the present study was to investigate the propofol effect on excitatory synaptic transmissions in cerebellar cortex.
Methods
Excitatory postsynaptic currents by parallel fiber stimulation and complex spikes by climbing fiber stimulation were monitored in Purkinje cells of Wister rat cerebellar slice using whole-cell patch-clamp techniques.
Results
Decay time, rise time and amplitude of excitatory postsynaptic currents at parallel fiber Purkinje cell synapses and area of complex spikes at climbing fiber Purkinje cell synapses were significantly increased by propofol administration.
Conclusion
The detected changes of glutamatergic synaptic transmission in cerebellar Purkinje cell, which determine cerebellar motor output, could explain cerebellar mechanism of motor deficits induced by propofol.
... Castejón et al. (2001a) and Castejón (2003a) described in detail a correlative conventional and high resolution SEM, and an immunochemical study of vertebrate Purkinje cells. Castejón and Dailey (2009) using confocal laser scanning microscopy (CLSM) showed the synaptic relationship of Purkinje cells by means of immunohistochemistry study of synapsin-I and PSD-95. Confocal microscopy, using Dil as a fluorescent stain permitted to observe also a continuous compartment of ER from the cell body throughout the dendrites (Terasaki et al., 1994). ...
... The axon of Purkinje cell emerges from the basal pole of the cell body. Calbindin and Cy5 labeling of rat cerebellar cortex (Castejón and Dailey, 2009) shows the course of Purkinje cell axons, and their collateral descending through the granular layer (Fig. 13). ...
... GluR1 is one of the several subunits of the subclass of quisqualate (QA) receptors coupled to cationic ionic channel, also termed AMPA receptors (Morrison et al., 1996;Crepel et al., 1996;Michaelis, 1996;Negyessy et al.,1997). GluR1 immunoreactivity was concentrated along the Purkinje and basket cell bodies and their dendritic arborization (Castejón and Dailey, 2009). Strong immunofluorescent staining was observed surrounding the Purkinje cell bodies corresponding to the enveloping Bergmann glial cell cytoplasm (Castejón, 2011) contributing to the formation of the pericellular nest, and to climbing fibers endings at the level of primary dendritic trunk (Castejón et al., 2000b). ...
The neuroimmune system of the brain, which is comprised primarily of astrocytes and microglia, regulates a variety of homeostatic mechanisms that underlie normal brain function. Numerous conditions, including alcohol consumption, can disrupt this regulatory process by altering brain levels of neuroimmune factors. Alcohol and neuroimmune factors, such as proinflammatory cytokines IL-6 and TNF-alpha, act at similar targets in the brain, including excitatory and inhibitory synaptic transmission. Thus, alcohol-induced production of IL-6 and/or TNF-alpha could be important contributing factors to the effects of alcohol on the brain. Recent studies indicate that IL-6 plays a role in alcohol drinking and the effects of alcohol on the brain activity following the cessation of alcohol consumption (post-alcohol period), however information on these topics is limited. Here we used homozygous and heterozygous female and male transgenic mice with increased astrocyte expression of IL-6 to examined further the interactions between alcohol and IL-6 with respect to voluntary alcohol drinking, brain activity during the post-alcohol period, IL-6 signal transduction, and expression of synaptic proteins. Wildtype littermates (WT) served as controls. The transgenic mice model brain neuroimmune status with respect to IL-6 in subjects with a history of persistent alcohol use. Results showed a genotype dependent reduction in voluntary alcohol consumption in the Drinking in the Dark protocol and in frequency-dependent relationships between brain activity in EEG recordings during the post-alcohol period and alcohol consumption. IL-6, TNF-alpha, IL-6 signal transduction partners pSTAT3 and c/EBP beta, and synaptic proteins were shown to play a role in these genotypic effects.
propuesto describir los episodios más trascendentes de mi vida académica como un legado a la juventud venezolana y latinoamericana. Tal vez como un ejemplo de lo que el ser humano puede lograr dentro del contexto social de un país en vías desarrollo, y con extensas áreas aún subdesarrolladas. La pasión por el conocimiento, el estudio permanente y sistemático y el trabajo creador nos permiten lograr un progresivo perfeccionamiento de nuestra condición humana. Contribución individual como aporte al desarrollo del país. Nuestros sueños e ideales pueden ser convertidos en realidades si perseveramos pacientemente en el logro de metas y destinos. Es posible además que la vida nos sorprenda dotándonos de posibilidades y oportunidades que no fueron avisoradas por nuestra imaginación. Podemos avanzar más alla de las fronteras de de nuestra imaginación creadora. Se requiere una profunda creencia y fé en la presencia divina rigiendo todos nuestros actos. En la realización de los dones que el Señor nos ha colocado en las regiones más recónditas de nuestro cerebro. En la proyección de nuestra mente hacia el entorno y el ambiente para capitalizar logros, vencer dificultades y superar obstáculos. Se requiere además, como mencionaba Don Santiago Ramón y Cajal, una fuerte ambición intelectual, espíritu patriótico y amor a la gloria.
This book provides a basic knowledge on the axospinodendritic contacts, multisynaptic o glomerular synapyic contacts, axosomatic synapses and axodendritic junctions in the normal cerebellar synapses, and in synaptic pathology of cerebral cortex, such as brain trauma, tumors, congenital hydrocephalus, and synaptic toxicity induced by dyphenilhydantoine and oil derivative like benzene. 4
