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![Distal dendritic b-APs and Ca2+ signals—LTP block.(a) Fluorescence image of an apical dendrite with a dendritic recording pipette and a stimulating electrode at a distance of 225 m from the soma (see also schematic). Scale bar, 20 m. (b) Changes in [Ca2+]i (top traces) in response to a train of four b-APs at 25 Hz (lower traces) elicited by antidromic stimulation were measured before (dotted lines, control) and after TBP in the presence of antagonists of the NMDA receptor (solid lines). The color of the traces corresponds to the colored boxes in a. In the presence of antagonists (50 M D,L-APV + 10 M MK-801) no changes were induced in the amplitude of b-APs or in the Ca2+ signals in the dendrite. (c) The changes in [Ca2+]i from the b-AP, 40 min after TBP, are plotted as a function of distance from the soma. (d) Potentiation of the EPSPs was blocked in the presence of NMDA receptor antagonists.](profile/Daniel-Johnston-4/publication/8914405/figure/fig6/AS:280225356238856@1443822339787/Distal-dendritic-b-APs-and-Ca2-signals-LTP-blocka-Fluorescence-image-of-an-apical.png)
Distal dendritic b-APs and Ca2+ signals—LTP block.(a) Fluorescence image of an apical dendrite with a dendritic recording pipette and a stimulating electrode at a distance of 225 m from the soma (see also schematic). Scale bar, 20 m. (b) Changes in [Ca2+]i (top traces) in response to a train of four b-APs at 25 Hz (lower traces) elicited by antidromic stimulation were measured before (dotted lines, control) and after TBP in the presence of antagonists of the NMDA receptor (solid lines). The color of the traces corresponds to the colored boxes in a. In the presence of antagonists (50 M D,L-APV + 10 M MK-801) no changes were induced in the amplitude of b-APs or in the Ca2+ signals in the dendrite. (c) The changes in [Ca2+]i from the b-AP, 40 min after TBP, are plotted as a function of distance from the soma. (d) Potentiation of the EPSPs was blocked in the presence of NMDA receptor antagonists.
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The propagation and integration of signals in the dendrites of pyramidal neurons is regulated, in part, by the distribution and biophysical properties of voltage-gated ion channels. It is thus possible that any modification of these channels in a specific part of the dendritic tree might locally alter these signaling processes. Using dendritic and...
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... repeated these experiments in the presence of NMDA receptor antagonists (50 µM D,L-APV + 10 µM MK-801; n = 2) to test whether the observed changes depended on LTP induction (Fig. 6). The b-APs (lower traces) were recorded at a distance of 225 µm from the soma, and the changes in the Ca 2+ signals (upper traces) from these b-APs were measured in this and neighboring dendritic regions (Fig. 6a,b). Blocking LTP induction prevented any changes in the amplitude of b- APs, the associated Ca 2+ signals in the dendrite ...
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... of NMDA receptor antagonists (50 µM D,L-APV + 10 µM MK-801; n = 2) to test whether the observed changes depended on LTP induction (Fig. 6). The b-APs (lower traces) were recorded at a distance of 225 µm from the soma, and the changes in the Ca 2+ signals (upper traces) from these b-APs were measured in this and neighboring dendritic regions (Fig. 6a,b). Blocking LTP induction prevented any changes in the amplitude of b- APs, the associated Ca 2+ signals in the dendrite (Fig. 6c) and the synaptic strength (Fig. 6d), suggesting that the measured modifica- tions of dendritic function are coupled to synaptic ...
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... (Fig. 6). The b-APs (lower traces) were recorded at a distance of 225 µm from the soma, and the changes in the Ca 2+ signals (upper traces) from these b-APs were measured in this and neighboring dendritic regions (Fig. 6a,b). Blocking LTP induction prevented any changes in the amplitude of b- APs, the associated Ca 2+ signals in the dendrite (Fig. 6c) and the synaptic strength (Fig. 6d), suggesting that the measured modifica- tions of dendritic function are coupled to synaptic ...
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... were recorded at a distance of 225 µm from the soma, and the changes in the Ca 2+ signals (upper traces) from these b-APs were measured in this and neighboring dendritic regions (Fig. 6a,b). Blocking LTP induction prevented any changes in the amplitude of b- APs, the associated Ca 2+ signals in the dendrite (Fig. 6c) and the synaptic strength (Fig. 6d), suggesting that the measured modifica- tions of dendritic function are coupled to synaptic ...
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... It is therefore not surprising that dendritic plasticity has been reported in pyramidal neurons within various brain regions in vivo, including the motor cortex [39], auditory cortex [12], hippocampus [40] and lateral amygdala [41] (figure 2). Typically occurring hand-in-hand with spine plasticity, plasticity can result in changes to both dendritic branching morphology [42] and/or dendritic signalling [43]. For example, the induction of LTP in hippocampal CA1 pyramidal neurons is accompanied by a local increase in dendritic excitability [43]. ...
... Typically occurring hand-in-hand with spine plasticity, plasticity can result in changes to both dendritic branching morphology [42] and/or dendritic signalling [43]. For example, the induction of LTP in hippocampal CA1 pyramidal neurons is accompanied by a local increase in dendritic excitability [43]. Various mechanisms have been shown to underlie local dendritic plasticity, including (i) local protein synthesis [44][45][46], (ii) ion channel density and distribution [47][48][49], (iii) contribution of intracellular calcium stores [40,50,51], (iv) intrinsic excitability [52][53][54] and (v) patterns of synaptic input [3,22,55,56]. ...
Neurons are plastic. That is, they change their activity according to different behavioural conditions. This endows pyramidal neurons with an incredible computational power for the integration and processing of synaptic inputs. Plasticity can be investigated at different levels of investigation within a single neuron, from spines to dendrites, to synaptic input. Although most of our knowledge stems from the in vitro brain slice preparation, plasticity plays a vital role during behaviour by providing a flexible substrate for the execution of appropriate actions in our ever-changing environment. Owing to advances in recording techniques, the plasticity of neurons and the neural networks in which they are embedded is now beginning to be realized in the in vivo intact brain. This review focuses on the structural and functional synaptic plasticity of pyramidal neurons, with a specific focus on the latest developments from in vivo studies.
This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on'.
... PKC participates in several intracellular signalling pathways that regulate neuronal function. These pathways can influence dendritic growth and branching (the receiving ends of neurons, neuronal circuit formation, and the overall functional connectivity of the brain) [43,44]. PKC is also involved in the control of presynaptic neurotransmitter release. ...
Protein kinase C (PKC) is a diverse enzyme family crucial for cell signalling in various organs. Its dysregulation is linked to numerous diseases, including cancer, cardiovascular disorders, and neurological problems. In the brain, PKC plays pivotal roles in synaptic plasticity, learning, memory, and neuronal survival. Specifically, PKC's involvement in Alzheimer's Disease (AD) path-ogenesis is of significant interest. The dysregulation of PKC signalling has been linked to neurolog-ical disorders, including AD. This review elucidates PKC's pivotal role in neurological health, particularly its implications in AD pathogenesis and chronic alcohol addiction. AD, characterised by neurodegeneration, implicates PKC dysregulation in synaptic dysfunction and cognitive decline. Conversely, chronic alcohol consumption elicits neural adaptations intertwined with PKC signalling , exacerbating addictive behaviours. By unravelling PKC's involvement in these afflictions, potential therapeutic avenues emerge, offering promise for ameliorating their debilitating effects. This review navigates the complex interplay between PKC, AD pathology, and alcohol addiction, illuminating pathways for future neurotherapeutic interventions.
... These measurements have been shown to undergo changes with various activity protocols. 15,[39][40][41][42][43][44][45] In conclusion, we show that tDCS exerts modulatory influence on dendritic physiology and that this effect is mostly confined to the distal region of the neuronal dendritic trunk. Moreover, our results show that these dendritic effects have potential implications for the long-term effects of tDCS and the manner by which tDCS exerts its clinical effects. ...
Transcranial direct current stimulation (tDCS) induces subcellular compartmental-dependent polarization, maximal in the distal portions of axons and dendrites. Using a morphologically realistic neuron model, we simulated tDCS-induced membrane polarization of the apical dendrite. Thus, we investigated the differential dendritic effects of anodal and cathodal tDCS on membrane potential polarization along the dendritic structure and its subsequent effects on dendritic membrane resistance, excitatory postsynaptic potential amplitude, backpropagating action potential amplitude, input/output relations, and long-term synaptic plasticity. We further showed that the effects of anodal and cathodal tDCS on the backpropagating action potential were asymmetric, and explained this asymmetry. Additionally, we showed that the effects on input/output relations were rather weak and limited to the low-mid range of stimulation frequencies, and that synaptic plasticity effects were mostly limited to the distal portion of the dendrite. Thus, we demonstrated how tDCS modifies dendritic physiology due to the dendrite’s unique morphology and composition of voltage-gated ion channels.
... Intrinsic plasticity is a long-lasting modification of intrinsic excitability that has been reported in various brain regions [1][2][3][4][5]. Being accompanied by synaptic plasticity, intrinsic plasticity can be induced bidirectionally [4,[6][7][8]. Previous studies have focused on changes in firing frequency to evaluate the magnitude of intrinsic plasticity, as this is the most representative feature of changes in neuronal excitability [4,7]. ...
Intrinsic plasticity of the cerebellar Purkinje cell (PC) plays a critical role in motor memory consolidation. However, detailed changes in their intrinsic properties during memory consolidation are not well understood. Here, we report alterations in various properties involved in intrinsic excitability, such as the action potential (AP) threshold, AP width, afterhyperpolarization (AHP), and sag voltage, which are associated with the long-term depression of intrinsic excitability following the motor memory consolidation process. We analyzed data recorded from PCs before and 1, 4, and 24 h after cerebellum-dependent motor learning and found that these properties underwent dynamic changes during the consolidation process. We further analyzed data from PC-specific STIM1 knockout (STIM1 PKO ) mice, which show memory consolidation deficits, and derived intrinsic properties showing distinct change patterns compared with those of wild-type littermates. The levels of memory retention in the STIM1 PKO mice were significantly different compared to wild-type mice between 1 and 4 h after training, and AP width, fast- and medium-AHP, and sag voltage showed different change patterns during this period. Our results provide information regarding alterations in intrinsic properties during a particular period that are critical for memory consolidation.
... Learning has been shown to increase the excitability of neurons participating in forming a given memory [110][111][112][113][114][115] . On the other hand, neurons with increased excitability are more likely to participate in the formation of a new memory engram 112,116,117 . ...
While artificial machine learning systems achieve superhuman performance in specific tasks such as language processing, image and video recognition, they do so use extremely large datasets and huge amounts of power. On the other hand, the brain remains superior in several cognitively challenging tasks while operating with the energy of a small lightbulb. We use a biologically constrained spiking neural network model to explore how the neural tissue achieves such high efficiency and assess its learning capacity on discrimination tasks. We found that synaptic turnover, a form of structural plasticity, which is the ability of the brain to form and eliminate synapses continuously, increases both the speed and the performance of our network on all tasks tested. Moreover, it allows accurate learning using a smaller number of examples. Importantly, these improvements are most significant under conditions of resource scarcity, such as when the number of trainable parameters is halved and when the task difficulty is increased. Our findings provide new insights into the mechanisms that underlie efficient learning in the brain and can inspire the development of more efficient and flexible machine learning algorithms.
... Kv4.2 K + channels are important regulators of dendritic excitability by mediating the transient A-current. Its membrane levels and phosphorylation status are regulated by electrical activity patterns used in LTP induction (e.g., strong TBS), suggesting that the activity of the channel, contributes to LTP expression (Frick et al., 2004;Kim and Hoffman, 2008;Rodrigues et al., 2021). Following EA, Kv4.2 levels ( Figure 6F) were reduced to 59.5 ± 11.1% (n = 5) after 0Mg 2+ exposure but were not significantly altered (98.8 ± 11.7%, n = 5) after Bic induced EA. ...
... Expression of Kv4.2 channels is more prominent in dendritic spines vs. dendritic shafts, being largely responsible for the Ca 2+ -activated delayed rectifying A-current (I A ) in CA1 pyramidal neuron distal dendrites, where it acts to control signal propagation and compartmentalization (Kim et al., 2007;Beck and Yaari, 2008;Kim and Hoffman, 2008). LTP induction with strong TBS stimuli reduces Kv4.2 dendritic membrane levels, leading to a shift in the voltage-dependence of I A , and Kv4.2 channel activity contributes to LTP expression (Frick et al., 2004;Kim and Hoffman, 2008). Kv4.2 channels are responsible for the precision of the time window of pre and postsynaptic activity allowed for LTP induction (Zhao et al., 2011) and I A activation also influences synaptic NMDA receptor composition at CA1 pyramidal neurons (Jung et al., 2008) and is synaptic morphology and seizure susceptibility (Tiwari et al., 2020). ...
Non-epileptic seizures are identified as a common epileptogenic trigger. Early metaplasticity following seizures may contribute to epileptogenesis by abnormally altering synaptic strength and homeostatic plasticity. We now studied how in vitro epileptiform activity (EA) triggers early changes in CA1 long-term potentiation (LTP) induced by theta-burst stimulation (TBS) in rat hippocampal slices and the involvement of lipid rafts in these early metaplasticity events. Two forms of EA were induced: (1) interictal-like EA evoked by Mg2+ withdrawal and K+ elevation to 6 mM in the superfusion medium or (2) ictal-like EA induced by bicuculline (10 μM). Both EA patterns induced and LTP-like effect on CA1 synaptic transmission prior to LTP induction. LTP induced 30 min post EA was impaired, an effect more pronounced after ictal-like EA. LTP recovered to control levels 60 min post interictal-like EA but was still impaired 60 min after ictal-like EA. The synaptic molecular events underlying this altered LTP were investigated 30 min post EA in synaptosomes isolated from these slices. EA enhanced AMPA GluA1 Ser831 phosphorylation but decreased Ser845 phosphorylation and the GluA1/GluA2 ratio. Flotillin-1 and caveolin-1 were markedly decreased concomitantly with a marked increase in gephyrin levels and a less prominent increase in PSD-95. Altogether, EA differentially influences hippocampal CA1 LTP thorough regulation of GluA1/GluA2 levels and AMPA GluA1 phosphorylation suggesting that altered LTP post-seizures is a relevant target for antiepileptogenic therapies. In addition, this metaplasticity is also associated with marked alterations in classic and synaptic lipid raft markers, suggesting these may also constitute promising targets in epileptogenesis prevention.
... In addition to shaping neuronal excitability, voltage-gated K + channels regulate synaptic transmission and plasticity as they are recruited during depolarization induced by synaptic events (Frick et al., 2004;Truchet et al., 2012). ...
Drug use poses a serious threat to health systems throughout the world. The number of consumers rises every year being alcohol the drug of abuse most consumed causing 3 million deaths (5.3% of all deaths) worldwide and 132.6 million disability-adjusted life years. In this review, we present an up-to-date summary about what is known regarding the global impact of binge alcohol drinking on brains and how it affects the development of cognitive functions, as well as the various preclinical models used to probe its effects on the neurobiology of the brain. This will be followed by a detailed report on the state of our current knowledge of the molecular and cellular mechanisms underlying the effects of binge drinking on neuronal excitability and synaptic plasticity, with an emphasis on brain regions of the meso-cortico limbic neurocircuitry.
... Kv4.2 K + channels are important regulators of dendritic excitability by mediating the transient A-current. Its membrane levels and phosphorylation status are regulated by electrical activity patterns used in LTP induction (e.g., strong TBS), suggesting that the activity of the channel, contributes to LTP expression (Frick et al., 2004;Kim and Hoffman, 2008;Rodrigues et al., 2021). Following EA, Kv4.2 levels ( Figure 6F) were reduced to 59.5 ± 11.1% (n = 5) after 0Mg 2+ exposure but were not significantly altered (98.8 ± 11.7%, n = 5) after Bic induced EA. ...
... Expression of Kv4.2 channels is more prominent in dendritic spines vs. dendritic shafts, being largely responsible for the Ca 2+ -activated delayed rectifying A-current (I A ) in CA1 pyramidal neuron distal dendrites, where it acts to control signal propagation and compartmentalization (Kim et al., 2007;Beck and Yaari, 2008;Kim and Hoffman, 2008). LTP induction with strong TBS stimuli reduces Kv4.2 dendritic membrane levels, leading to a shift in the voltage-dependence of I A , and Kv4.2 channel activity contributes to LTP expression (Frick et al., 2004;Kim and Hoffman, 2008). Kv4.2 channels are responsible for the precision of the time window of pre and postsynaptic activity allowed for LTP induction (Zhao et al., 2011) and I A activation also influences synaptic NMDA receptor composition at CA1 pyramidal neurons (Jung et al., 2008) and is synaptic morphology and seizure susceptibility (Tiwari et al., 2020). ...
Non-epileptic seizures are identified as a common epileptogenic trigger. Early metaplasticity following seizures may contribute to epileptogenesis by abnormally altering synaptic strength and homeostatic plasticity. We now studied how in vitro epileptiform activity triggers early changes in CA1 long-term potentiation (LTP) induced by theta-burst stimulation (TBS) in rat hippocampal slices and the involvement of lipid rafts in these early metaplasticity events. Two forms of epileptiform activity (EA) were induced: 1) interictal-like EA triggered by withdrawal of Mg ²⁺ and K ⁺ elevation to 6mM in the superfusion medium or 2) ictal-like EA induced by bicuculine (10μM) delivery. LTP induced 30 min post EA was impaired, an effect more pronounced after ictal-like EA. LTP recovered to control levels 60 min post interictal-like EA but was still impaired 60 min after ictal-like EA. The synaptic molecular events underlying this altered LTP were investigated 30 min post EA. Synaptosomes isolated from parallel slices showed enhanced AMPA GluA1 Ser831 phosphorylation but decreased Ser 845 phosphorylation and a marked decrease in GluA1/GluA2 ratio. A marked decrease in flotillin-1 and caveolin-1 levels concomitantly with a moderate increase in PSD-95 and marked increase in gephyrin levels.
Altogether, EA differentially influences hippocampal CA1 LTP thorough regulation of GluA1/GluA2 levels and AMPA GluA1 phosphorylation suggesting altered LTP post-seizures may be a relevant target of antiepileptogenic therapies. In addition, this metaplasticity is also associated with marked alterations in classic and synaptic lipid raft markers, suggesting these may also constitute promising targets in epileptogenesis prevention.
... On the other hand, our observation that the pharmacological blockade of voltage-gated potassium channels unmasks dendritic calcium electrogenesis in human and rat L2/ 3 PNs suggests that differences between our and previous work (Gidon et al., 2020) may, in part, be explained by the differential regulation of potassium channel function. Consistent with this idea, the membrane expression and voltage-dependent availability of voltage-gated potassium channels are known to be controlled by a variety of factors such as neuronal activity (Frick et al., 2004;Kim et al., 2007;Sandler et al., 2016), osmolarity (Caspi et al., 2009), intracellular calcium , and neuromodulators (Hoffman and Johnston, 1998), and so may have been downregulated in previous investigation of HL2/3 PNs (Gidon et al., 2020). Such an interpretation may help to explain the narrow range over which excitatory input was reported to generate dendritic calcium spikes in HL2/3 PNs but does not explain why previous investigation failed to detect the existence of TTX-sensitive dendritic spikes (Gidon et al., 2020). ...
Dendritic spikes function as cardinal components of rodent neocortical circuit computations. Recently, the biophysical properties of human pyramidal neurons (PNs) have been reported to be divergent, raising the question of whether dendritic spikes have homologous roles in the human neocortex. To directly address this, we made electrical recordings from the soma and apical dendrites of human and rat layer 2/3 PNs of the temporal cortex. In both species, dendritic excitatory input led to the initiation of sodium-channel-mediated dendritic spikes. Dendritic sodium spikes could be generated across a wide input range, exhibited a similar frequency range of activation, and forward-propagated with high-fidelity to implement stereotyped computations in human and rat PNs. However, the physical expansion and complexification of the apical dendritic trees of human PNs allowed the enriched expression of dendritic spike generation. The computational capacity of human PNs is therefore enhanced by the widespread implementation of a conserved dendritic integration mechanism.
... 1. Intracellular biochemical milieu, upon which cellular processes are heavily dependent and receive continuous perturbations (Marder and Thirumalai, 2002;Desai, 2003;Frick et al., 2004;Turrigiano and Nelson, 2004;Fan et al., 2005). 2. Various ion channels, which define basic neuronal properties undergo continuous trafficking at the plasma membrane (Lai and Jan, 2006;Shepherd and Huganir, 2007;Vacher et al., 2008;Shah et al., 2010;Nusser, 2012). ...
The prerequisites for neurons to function within a circuit and be able to contain and transfer information efficiently and reliably are that they need to be homeostatically stable and fire within a reasonable range, characteristics that are governed, among others, by voltage-gated ion channels (VGICs). Nonetheless, neurons entail large variability in the expression levels of VGICs and their corresponding intrinsic properties, but the role of this variability in information transfer is not fully known. In this study, we aimed to investigate how this variability of VGICs affects information transfer. For this, we used a previously derived population of neuronal model neurons, each with the variable expression of five types of VGICs, fast Na+, delayed rectifier K+, A-type K+, T-type Ca++, and HCN channels. These analyses showed that the model neurons displayed variability in mutual information transfer, measured as the capability of neurons to successfully encode incoming synaptic information in output firing frequencies. Likewise, variability in the expression of VGICs caused variability in EPSPs and IPSPs amplitudes, reflected in the variability of output firing frequencies. Finally, using the virtual knockout methodology, we show that among the ion channels tested, the A-type K+ channel is the major regulator of information processing and transfer.
