scholarly journals Acetylcholine boosts dendritic NMDA spikes in a CA3 pyramidal neuron model

2021 ◽  
Author(s):  
Rachel Humphries ◽  
Jack R. Mellor ◽  
Cian O’Donnell
Keyword(s):  
Potassium Channels ◽  
Computational Models ◽  
Pyramidal Neurons ◽  
Input Resistance ◽  
Synaptic Integration ◽  
Stratum Radiatum ◽  
List Type ◽  
Spike Generation ◽  
Dendritic Excitability ◽  
Nmdar Activation

AbstractAcetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca2+ influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of acetylcholine on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca2+-activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles.Highlights-Using biophysical computational models of CA3 pyramidal neurons we estimated the quantitative effects of acetylcholine on nonlinear synaptic integration.-Nonlinear NMDA spikes can be triggered by fewer synapses in distal dendrites due to increased local input resistance.-Acetylcholine broadly reduces the number of synapses needed to trigger NMDA spikes, but the magnitude of the effect varies across dendrite branches within a single neuron.-No single potassium channel type is the dominant mediator of the excitability effects of acetylcholine.

scholarly journals Somatic and dendritic GABAB receptors regulate neuronal excitability via different mechanisms

2012 ◽  
Vol 108 (10) ◽  
pp. 2810-2818 ◽  
Author(s):  
Jean-Didier Breton ◽  
Greg J. Stuart
Keyword(s):  
Potassium Channels ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Barrel Cortex ◽  
Receptor Activation ◽  
Gabab Receptors ◽  
Membrane Properties ◽  
Dendritic Excitability ◽  
The Impact ◽  
Neuronal Output

GABAB receptors play a key role in regulating neuronal excitability in the brain. Whereas the impact of somatic GABAB receptors on neuronal excitability has been studied in some detail, much less is known about the role of dendritic GABAB receptors. Here, we investigate the impact of GABAB receptor activation on the somato-dendritic excitability of layer 5 pyramidal neurons in the rat barrel cortex. Activation of GABAB receptors led to hyperpolarization and a decrease in membrane resistance that was greatest at somatic and proximal dendritic locations. These effects were occluded by low concentrations of barium (100 μM), suggesting that they are mediated by potassium channels. In contrast, activation of dendritic GABAB receptors decreased the width of backpropagating action potential (APs) and abolished dendritic calcium electrogenesis, indicating that dendritic GABAB receptors regulate excitability, primarily via inhibition of voltage-dependent calcium channels. These distinct actions of somatic and dendritic GABAB receptors regulated neuronal output in different ways. Activation of somatic GABAB receptors led to a reduction in neuronal output, primarily by increasing the AP rheobase, whereas activation of dendritic GABAB receptors blocked burst firing, decreasing AP output in the absence of a significant change in somatic membrane properties. Taken together, our results show that GABAB receptors regulate somatic and dendritic excitability of cortical pyramidal neurons via different cellular mechanisms. Somatic GABAB receptors activate potassium channels, leading primarily to a subtractive or shunting form of inhibition, whereas dendritic GABAB receptors inhibit dendritic calcium electrogenesis, leading to a reduction in bursting firing.

scholarly journals Active dendrites, potassium channels and synaptic plasticity

2003 ◽  
Vol 358 (1432) ◽  
pp. 667-674 ◽  
Author(s):  
Daniel Johnston ◽  
Brian R. Christie ◽  
Andreas Frick ◽  
Richard Gray ◽  
Dax A. Hoffman ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Potassium Channels ◽  
Potassium Channel ◽  
Pyramidal Neurons ◽  
Back Propagation ◽  
Dendritic Tree ◽  
Long Term Potentiation ◽  
Synaptic Potentials ◽  
Dendritic Excitability

The dendrites of CA1 pyramidal neurons in the hippocampus express numerous types of voltage-gated ion channel, but the distributions or densities of many of these channels are very non-uniform. Sodium channels in the dendrites are responsible for action potential (AP) propagation from the axon into the dendrites (back-propagation); calcium channels are responsible for local changes in dendritic calcium concentrations following back-propagating APs and synaptic potentials; and potassium channels help regulate overall dendritic excitability. Several lines of evidence are presented here to suggest that back-propagating APs, when coincident with excitatory synaptic input, can lead to the induction of either long-term depression (LTD) or long-term potentiation (LTP). The induction of LTD or LTP is correlated with the magnitude of the rise in intracellular calcium. When brief bursts of synaptic potentials are paired with postsynaptic APs in a theta-burst pairing paradigm, the induction of LTP is dependent on the invasion of the AP into the dendritic tree. The amplitude of the AP in the dendrites is dependent, in part, on the activity of a transient, A-type potassium channel that is expressed at high density in the dendrites and correlates with the induction of the LTP. Furthermore, during the expression phase of the LTP, there are local changes in dendritic excitability that may result from modulation of the functioning of this transient potassium channel. The results support the view that the active properties of dendrites play important roles in synaptic integration and synaptic plasticity of these neurons.

scholarly journals Impact of calcium-activated potassium channels on NMDA spikes in cortical layer 5 pyramidal neurons

2016 ◽  
Vol 115 (3) ◽  
pp. 1740-1748 ◽  
Author(s):  
Tobias Bock ◽  
Greg J. Stuart
Keyword(s):  
Potassium Channels ◽  
Calcium Channels ◽  
Pyramidal Neurons ◽  
Cortical Layer ◽  
Sk Channels ◽  
Spike Generation ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Basal Dendrites ◽  
Calcium Activated Potassium Channels

Active electrical events play an important role in shaping signal processing in dendrites. As these events are usually associated with an increase in intracellular calcium, they are likely to be under the control of calcium-activated potassium channels. Here, we investigate the impact of calcium-activated potassium channels on N-methyl-d-aspartate (NMDA) receptor-dependent spikes, or NMDA spikes, evoked by glutamate iontophoresis onto basal dendrites of cortical layer 5 pyramidal neurons. We found that small-conductance calcium-activated potassium channels (SK channels) act to reduce NMDA spike amplitude but at the same time, also decrease the iontophoretic current required for their generation. This SK-mediated decrease in NMDA spike threshold was dependent on R-type voltage-gated calcium channels and indicates a counterintuitive, excitatory effect of SK channels on NMDA spike generation, whereas the capacity of SK channels to suppress NMDA spike amplitude is in line with the expected inhibitory action of potassium channels on dendritic excitability. Large-conductance calcium-activated potassium channels had no significant impact on NMDA spikes, indicating that these channels are either absent from basal dendrites or not activated by NMDA spikes. These experiments reveal complex and opposing interactions among NMDA receptors, SK channels, and voltage-gated calcium channels in basal dendrites of cortical layer 5 pyramidal neurons during NMDA spike generation, which are likely to play an important role in regulating the way these neurons integrate the thousands of synaptic inputs they receive.

scholarly journals High levels of 27-hydroxycholesterol results in synaptic plasticity alterations in the hippocampus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raul Loera-Valencia ◽  
Erika Vazquez-Juarez ◽  
Alberto Muñoz ◽  
Gorka Gerenu ◽  
Marta Gómez-Galán ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Memory Function ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Cholesterol Homeostasis ◽  
Stratum Radiatum ◽  
Actin Binding ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Term Potentiation

AbstractAlterations in brain cholesterol homeostasis in midlife are correlated with a higher risk of developing Alzheimer’s disease (AD). However, global cholesterol-lowering therapies have yielded mixed results when it comes to slowing down or preventing cognitive decline in AD. We used the transgenic mouse model Cyp27Tg, with systemically high levels of 27-hydroxycholesterol (27-OH) to examine long-term potentiation (LTP) in the hippocampal CA1 region, combined with dendritic spine reconstruction of CA1 pyramidal neurons to detect morphological and functional synaptic alterations induced by 27-OH high levels. Our results show that elevated 27-OH levels lead to enhanced LTP in the Schaffer collateral-CA1 synapses. This increase is correlated with abnormally large dendritic spines in the stratum radiatum. Using immunohistochemistry for synaptopodin (actin-binding protein involved in the recruitment of the spine apparatus), we found a significantly higher density of synaptopodin-positive puncta in CA1 in Cyp27Tg mice. We hypothesize that high 27-OH levels alter synaptic potentiation and could lead to dysfunction of fine-tuned processing of information in hippocampal circuits resulting in cognitive impairment. We suggest that these alterations could be detrimental for synaptic function and cognition later in life, representing a potential mechanism by which hypercholesterolemia could lead to alterations in memory function in neurodegenerative diseases.

scholarly journals Computational Analysis of the Impact of Chronic Stress on Intrinsic and Synaptic Excitability in the Hippocampus

2010 ◽  
Vol 103 (6) ◽  
pp. 3070-3083 ◽  
Author(s):  
Rishikesh Narayanan ◽  
Sumantra Chattarji
Keyword(s):  
Chronic Stress ◽  
Pyramidal Neurons ◽  
Three Dimensional ◽  
Input Resistance ◽  
Synaptic Potentiation ◽  
Synaptic Inputs ◽  
Hippocampal Ca3 ◽  
Ca3 Pyramidal Neurons ◽  
Dendritic Atrophy ◽  
The Impact

Dendritic atrophy and impaired long-term synaptic potentiation (LTP) are hallmarks of chronic stress-induced plasticity in the hippocampus. It has been hypothesized that these disparate structural and physiological correlates of stress lead to hippocampal dysfunction by reducing postsynaptic dendritic surface, thereby adversely affecting the availability of synaptic inputs and suppressing LTP. Here we examine the validity of this framework using biophysical models of hippocampal CA3 pyramidal neurons. To statistically match with the experimentally observed region specificity of stress-induced atrophy, we use an algorithm to systematically prune three-dimensional reconstructions of CA3 pyramidal neurons. Using this algorithm, we build a biophysically realistic computational model to analyze the effects of stress on intrinsic and synaptic excitability. We find that stress-induced atrophy of CA3 dendrites leads to an increase in input resistance, which depends exponentially on the percentage of neuronal atrophy. This increase translates directly into higher spiking frequencies in response to both somatic current injections and synaptic inputs at various locations along the dendritic arbor. Remarkably, we also find that the dendritic regions that manifest atrophy-induced synaptic hyperexcitability are governed by the region specificity of the underlying dendritic atrophy. Coupled with experimentally observed modulation of N-methyl-d-aspartate receptor currents, such hyperexcitability could tilt the balance of plasticity mechanisms in favor of synaptic potentiation over depression. Thus paradoxically, our results suggest that stress may impair hippocampal learning and memory, not by directly inhibiting LTP, but because of stress-induced facilitation of intrinsic and synaptic excitability and the consequent imbalance in bidirectional synaptic plasticity.

Differential Impact of Miniature Synaptic Potentials on the Soma and Dendrites of Pyramidal Neurons In Vivo

1997 ◽  
Vol 78 (3) ◽  
pp. 1735-1739 ◽  
Author(s):  
Denis Paré ◽  
Elen Lebel ◽  
Eric J. Lang
Keyword(s):  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Differential Impact ◽  
Synaptic Potentials ◽  
Ampa Antagonists ◽  
Intact Brain ◽  
The Impact

Paré, Denis, Elen LeBel, and Eric J. Lang. Differential impact of miniature synaptic potentials on the somata and dendrites of pyramidal neurons in vivo. J. Neurophysiol. 78: 1735–1739, 1997. We studied the impact of transmitter release resistant to tetrodotoxin (TTX) in morphologically identified neocortical pyramidal neurons recorded intracellularly in barbiturate-anesthetized cats. It was observed that TTX-resistant release occurs in pyramidal neurons in vivo and at much higher frequencies than was previously reported in vitro. Further, in agreement with previous findings indicating that GABAergic and glutamatergic synapses are differentially distributed in the somata and dendrites of pyramidal cells, we found that most miniature synaptic potentials were sensitive to γ-aminobutyric acid-A (GABAA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists in presumed somatic and dendritic impalements, respectively. Pharmacological blockage of spontaneous synaptic events produced large increases in input resistance that were more important in dendritic (≈50%) than somatic (≈10%) impalements. These findings imply that in the intact brain, pyramidal neurons are submitted to an intense spike-independent synaptic bombardment that decreases the space constant of the cells. These results should be taken into account when extrapolating in vitro findings to intact brains.

scholarly journals Apical length governs computational diversity of L5 pyramidal neurons

2019 ◽  
Author(s):  
Alessandro R. Galloni ◽  
Aeron Laffere ◽  
Ede Rancz
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Apical Dendrite ◽  
Common Assumption ◽  
Dendritic Excitability ◽  
Visual Cortices ◽  
The Common ◽  
Channel Dependent ◽  
Apical Dendrites ◽  
The Brain

AbstractAnatomical similarity across the neocortex has led to the common assumption that the circuitry is modular and performs stereotyped computations. Layer 5 pyramidal neurons (L5PNs) in particular are thought to be central to cortical computation because of their extensive arborisation and nonlinear dendritic operations. Here, we demonstrate that computations associated with dendritic Ca2+ plateaus in L5PNs vary substantially between the primary and secondary visual cortices. L5PNs in the secondary visual cortex show reduced dendritic excitability and smaller propensity for burst firing. This reduced excitability is correlated with shorter apical dendrites. Using numerical modelling, we uncover a universal principle underlying the influence of apical length on dendritic backpropagation and excitability, based on a Na+ channel-dependent broadening of backpropagating action potentials. In summary, we provide new insights into the modulation of dendritic excitability by apical dendrite length and show that the operational repertoire of L5 neurons is not universal throughout the brain.

scholarly journals Astrocytic modulation of information processing by layer 5 pyramidal neurons of the mouse visual cortex

2020 ◽  
Author(s):  
Dimitri Ryczko ◽  
Maroua Hanini-Daoud ◽  
Steven Condamine ◽  
Benjamin J. B. Bréant ◽  
Maxime Fougère ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Cortical Neurons ◽  
Calcium Binding ◽  
Pyramidal Neurons ◽  
Binding Protein ◽  
Contextual Information ◽  
Dendritic Tree ◽  
Cortical Layer ◽  
List Type ◽  
Ionic Environment

AbstractThe most complex cerebral functions are performed by the cortex which most important output is carried out by its layer 5 pyramidal neurons. Their firing reflects integration of sensory and contextual information that they receive. There is evidence that astrocytes influence cortical neurons firing through the release of gliotransmitters such as ATP, glutamate or GABA. These effects were described at the network and at the synaptic levels, but it is still unclear how astrocytes influence neurons input-output transfer function at the cellular level. Here, we used optogenetic tools coupled with electrophysiological, imaging and anatomical approaches to test whether and how astrocytic activation affected processing and integration of distal inputs to layer 5 pyramidal neurons (L5PN). We show that optogenetic activation of astrocytes near L5PN cell body prolonged firing induced by distal inputs to L5PN and potentiated their ability to trigger spikes. The observed astrocytic effects on L5PN firing involved glutamatergic transmission to some extent but relied on release of S100β, an astrocytic Ca2+-binding protein that decreases extracellular Ca2+ once released. This astrocyte-evoked decrease of extracellular Ca2+ elicited firing mediated by activation of Nav1.6 channels. Our findings suggest that astrocytes contribute to the cortical fundamental computational operations by controlling the extracellular ionic environment.Key Points SummaryIntegration of inputs along the dendritic tree of layer 5 pyramidal neurons is an essential operation as these cells represent the most important output carrier of the cerebral cortex. However, the contribution of astrocytes, a type of glial cell to these operations is poorly documented.Here we found that optogenetic activation of astrocytes in the vicinity of layer 5 in the mouse primary visual cortex induce spiking in local pyramidal neurons through Nav1.6 ion channels and prolongs the responses elicited in these neurons by stimulation of their distal inputs in cortical layer 1.This effect partially involved glutamatergic signalling but relied mostly on the astrocytic calcium-binding protein S100β, which regulates the concentration of calcium in the extracellular space around neurons.These findings show that astrocytes contribute to the fundamental computational operations of the cortex by acting on the ionic environment of neurons.

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