Dendritic Excitability and Gain Control in Recurrent Cortical Microcircuits

Hay, Etay; Segev, Idan

doi:10.1093/cercor/bhu200

Cited by 61 publications

(105 citation statements)

References 85 publications

(142 reference statements)

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“…Although the analyses presented in this article are specific to L5PCs and SCZ-related genes, our framework may be directly applicable to other cell types and other polygenic diseases, such as bipolar disorder and autism, given an identification of risk genes related to neuronal excitability. Furthermore, our approach can be directly extended to biophysically detailed models of neuronal networks, e.g., Hay and Segev (24). …”

Section: Discussionmentioning

confidence: 99%

Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single-Neuron Excitability: A Modeling Study

Mäki‐Marttunen

Halnes

Devor

et al. 2016

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

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Background Recent genome-wide association studies have identified a large number of genetic risk factors for schizophrenia (SCZ) featuring ion channels and calcium transporters. For some of these risk factors, independent prior investigations have examined the effects of genetic alterations on the cellular electrical excitability and calcium homeostasis. In the present proof-of-concept study, we harnessed these experimental results for modeling of computational properties on layer V cortical pyramidal cells and identified possible common alterations in behavior across SCZ-related genes. Methods We applied a biophysically detailed multicompartmental model to study the excitability of a layer V pyramidal cell. We reviewed the literature on functional genomics for variants of genes associated with SCZ and used changes in neuron model parameters to represent the effects of these variants. Results We present and apply a framework for examining the effects of subtle single nucleotide polymorphisms in ion channel and calcium transporter-encoding genes on neuron excitability. Our analysis indicates that most of the considered SCZ-related genetic variants affect the spiking behavior and intracellular calcium dynamics resulting from summation of inputs across the dendritic tree. Conclusions Our results suggest that alteration in the ability of a single neuron to integrate the inputs and scale its excitability may constitute a fundamental mechanistic contributor to mental disease, alongside the previously proposed deficits in synaptic communication and network behavior.

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Section: Discussionmentioning

confidence: 99%

Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single-Neuron Excitability: A Modeling Study

Mäki‐Marttunen

Halnes

Devor

et al. 2016

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

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“…As a common cell type in mammalian brain, pyramidal neurons have been studied with theoretical approaches that incorporate dendritic Ca 2+ channel in multi-compartmental models213334353637. These complex models may express more than 10 voltage-gated channels, which are non-homegenously distributed along the somato-dendritic axis.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to above in vitro observations, there are also modeling studies that focus on the dendritic Ca 2+ activity213334353637. Most of them use biophysically realistic neurons that are modeled in NEURON or GENESIS to understand the mechanism underlying the generation and propagation of dendritic Ca 2+ spike.…”

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confidence: 99%

Action potential initiation in a two-compartment model of pyramidal neuron mediated by dendritic Ca2+ spike

Wang

Wei

et al. 2017

Sci Rep

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Dendritic Ca2+ spike endows cortical pyramidal cell with powerful ability of synaptic integration, which is critical for neuronal computation. Here we propose a two-compartment conductance-based model to investigate how the Ca2+ activity of apical dendrite participates in the action potential (AP) initiation to affect the firing properties of pyramidal neurons. We have shown that the apical input with sufficient intensity triggers a dendritic Ca2+ spike, which significantly boosts dendritic inputs as it propagates to soma. Such event instantaneously shifts the limit cycle attractor of the neuron and results in a burst of APs, which makes its firing rate reach a plateau steady-state level. Delivering current to two chambers simultaneously increases the level of neuronal excitability and decreases the threshold of input-output relation. Here the back-propagating APs facilitate the initiation of dendritic Ca2+ spike and evoke BAC firing. These findings indicate that the proposed model is capable of reproducing in vitro experimental observations. By determining spike initiating dynamics, we have provided a fundamental link between dendritic Ca2+ spike and output APs, which could contribute to mechanically interpreting how dendritic Ca2+ activity participates in the simple computations of pyramidal neuron.

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“…Finally, in Section 3.4, we used a multicompartmental model of a layer 2/3 pyramidal cell [Markram et al, 2015] (L23 PC cADpyr229 5) to determine the amplitudes and time courses of the Ca 2+ inputs conducted by NMDA receptors (NMDARs) when different pairing intervals were applied. We used the probabilistic AMPA-NMDA synapse model of [Hay and Segev, 2015] with the NMDA gating mechanism of [Spruston et al, 1995], a correction in the pre-synaptic resource update [Mäki-Marttunen et al, 2018] and an AMPA-NMDA ratio of 1:7. We estimated the numbers of Ca 2+ ions entering into post-synaptic spines consisting of a 0.5 µm long and 0.1 µm thick neck and a 0.4 µm long and 0.4 µm thick head across time, and used these numbers as the input to the biochemical model.…”

Section: Modelling the Ca 2+ Inputs And Neuromodulatory Inputsmentioning

confidence: 99%

“…We placed a synaptic spine with volume 0.5 µm 3 at a random location on the apical dendrite, 250-300 µm from the soma (Fig. 6A, thick, black branches), and stimulated the head of the spine with glutamatergic synaptic currents [Hay andSegev, 2015, Markram et al, 2015] (Fig. 6A, black traces, top).…”

Section: High-frequency Stimulation Causes Ltp and Low-frequency Stimmentioning

confidence: 99%

A unified computational model for cortical post-synaptic plasticity

Mäki‐Marttunen

Iannella

Edwards

et al. 2020

Preprint

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Cortical synapses possess a machinery of signalling pathways that leads to various modes of post-synaptic plasticity. Such pathways have been examined to a great detail separately in many types of experimental studies. However, a unified picture on how multiple biochemical pathways collectively shape the observed synaptic plasticity in the neocortex is missing. Here, we built a biochemically detailed model of post-synaptic plasticity that includes the major signalling cascades, namely, CaMKII, PKA, and PKC pathways which, upon activation by Ca 2+ , lead to synaptic potentiation or depression. We adjusted model components from existing models of intracellular signalling into a single-compartment simulation framework. Furthermore, we propose a statistical model for the prevalence of different types of membrane-bound AMPA-receptor tetramers consisting of GluR1 and GluR2 subunits in proportions suggested by the biochemical signalling model, which permits the estimation of the AMPA-receptor-mediated maximal synaptic conductance. We show that our model can reproduce neuromodulator-gated spike-timing-dependent plasticity as observed in the visual cortex. Moreover, we demonstrate that our model can be fit to data from many cortical areas and that the resulting model parameters reflect the involvement of the pathways pinpointed by the underlying experimental studies. Our model explains the dependence of different forms of plasticity on the availability of different proteins and can be used for the study of mental disorder-associated impairments of cortical plasticity. Significance statementNeocortical synaptic plasticity has been studied experimentally in a number of cortical areas, showing how interactions between neuromodulators and post-synaptic proteins shape the outcome of the plasticity. On the other hand, non-detailed computational models of long-term plasticity, such as Hebbian rules of synaptic potentiation and depression, have been widely used in modelling of neocortical circuits. In this work, we bridge the gap between these two branches of neuroscience by building a detailed model of post-synaptic plasticity that can reproduce observations on cortical plasticity and provide biochemical meaning to the simple rules of plasticity. Our model can be used for predicting the effects of chemical or genetic manipulations of various intracellular signalling proteins on induction of plasticity in health and disease.

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Dendritic Excitability and Gain Control in Recurrent Cortical Microcircuits

Cited by 61 publications

References 85 publications

Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single-Neuron Excitability: A Modeling Study

Functional Effects of Schizophrenia-Linked Genetic Variants on Intrinsic Single-Neuron Excitability: A Modeling Study

Action potential initiation in a two-compartment model of pyramidal neuron mediated by dendritic Ca2+ spike

A unified computational model for cortical post-synaptic plasticity

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