Action Potential Initiation in Neocortical Inhibitory Interneurons

Li, Tun; Tian, Cuiping; Scalmani, Paolo; Frassoni, Carolina; Mantegazza, Massimo; Wang, Yonghong; Yang, Mingpo; Wu, Si; Shu, Yousheng

doi:10.1371/journal.pbio.1001944

Cited by 112 publications

(118 citation statements)

References 60 publications

(106 reference statements)

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“…If this hypothesis were correct, we would expect the missense variants observed in ASD to reduce Na V 1.2 channel function and decrease neuron excitability. We therefore performed functional analyses of all 12 de novo SCN2A mutations observed in the 4,109 ASD cases from the Simons Simplex Collection (SSC; 2,508 families with a single affected child) and Autism Sequencing Consortium (ASC; 1,601 families with one or more affected children), as these cases were identified as representing idiopathic ASD in clearly defined cohorts (4, 9, 22). …”

Section: Resultsmentioning

confidence: 99%

“…Though the majority of cortical interneurons express SCN1A /Na V 1.1 at the AIS (46, 47), with loss of function resulting in Dravet Syndrome with EE (48), somatostatin positive interneurons, which play a role in cortical circuit maturation (49, 50), express a mix of both Na V 1.1 and 1.2 in the proximal AIS (9). Further, Na V 1.2 channels are expressed throughout cerebellar granule cell axons (8), potentially contributing to episodic ataxia (25).…”

Section: Discussionmentioning

confidence: 99%

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Opposing Effects on Na V 1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures

Ben-Shalom

Keeshen²,

Berríos

et al. 2017

Biological Psychiatry

228

313

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BACKGROUND Variants in SCN2A that disrupt the encoded neuronal sodium channel NaV1.2 are important risk factors for autism spectrum disorder (ASD), developmental delay, and infantile seizures. Variants observed in infantile seizures are predominantly missense, leading to a gain of function and increased neuronal excitability. How variants associated with ASD affect NaV1.2 function and neuronal excitability are unclear. METHODS We examined the properties of 11 ASD-associated SCN2A variants in heterologous expression systems using whole-cell voltage-clamp electrophysiology and immunohistochemistry. Resultant data were incorporated into computational models of developing and mature cortical pyramidal cells that express NaV1.2. RESULTS In contrast to gain of function variants that contribute to seizure, we found that all ASD-associated variants dampened or eliminated channel function. Incorporating these electrophysiological results into a compartmental model of developing excitatory neurons demonstrated that all ASD variants, regardless of their mechanism of action, resulted in deficits in neuronal excitability. Corresponding analysis of mature neurons predicted minimal change in neuronal excitability. CONCLUSIONS This functional characterization thus identifies SCN2A mutation and NaV1.2 dysfunction as the most frequently observed ASD risk factor detectable by exome sequencing and suggests that associated changes in neuronal excitability, particularly in developing neurons, may contribute to ASD etiology.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Opposing Effects on Na V 1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures

Ben-Shalom

Keeshen²,

Berríos

et al. 2017

Biological Psychiatry

228

313

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“…Mutations in the genes encoding the Na v 1.1 channels can cause Dravet syndrome and other types of infantile epilepsy [63] . In both PV and SST interneurons, Na v 1.6 channels were found in the distal part of the AIS, whereas Na v 1.2 channels were found in the proximal part of the AIS only in SST-positive INs [60] . A recent study showed that, in human cortical pyramidal cells, the pattern of Na + channel distribution is similar to that in rodents [64] .…”

Section: Na + Channelsmentioning

confidence: 93%

“…Other study suggests, however, that the distribution of Na v 1.6 within the AIS is more uniform [42] . Na v 1.1 channels are found in the proximal part of the AIS of the parvalbumin (PV)-and somatostatin (SST)-positive GABAergic interneurons [60] of the neocortex and cerebellum [42] , in retinal ganglion cells [61] and in spinal cord motor neurons [62] . Mutations in the genes encoding the Na v 1.1 channels can cause Dravet syndrome and other types of infantile epilepsy [63] .…”

Section: Na + Channelsmentioning

confidence: 99%

Functional implications of axon initial segment cytoskeletal disruption in stroke

Stoler

Fleidervish

2015

Acta Pharmacol Sin

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Axon initial segment (AIS) is the proximal part of the axon, which is not covered with a myelin sheath and possesses a distinctive, specialized assembly of voltage-gated ion channels and associated proteins. AIS plays critical roles in synaptic integration and action potential generation in central neurons. Recent evidence shows that stroke causes rapid, irreversible calpain-mediated proteolysis of the AIS cytoskeleton of neurons surrounding the ischemic necrotic core. A better understanding of the molecular mechanisms underlying this "non-lethal" neuronal damage might provide new therapeutic strategies for improving stroke outcome. Here, we present a brief overview of the structure and function of the AIS. We then discuss possible mechanisms underlying stroke-induced AIS damage, including the roles of calpains and possible sources of Ca 2+ ions, which are necessary for the activation of calpains. Finally, we discuss the potential functional implications of the loss of the AIS cytoskeleton and ion channel clusters for neuronal excitability.

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“…Dysfunction in one or more of these inhibitory neuron populations can disrupt both the feedback and feedforward inhibitory circuitry, resulting in epilepsy disorders (Khoshkhoo et al, 2017;Paz and Huguenard, 2015). NAV1.1 is predominantly localized in the soma and in the axon initiating segment of PV-positive neurons (Ogiwara et al, 2007) and to lesser extent in SST and VIP neurons (Goff and Goldberg, 2019;Li et al, 2014;Ogiwara et al, 2007;Tai et al, 2014). Reduced excitability of PV neurons has been implicated in hyperexcitable circuits in Scn1a mouse models of DS and GEFS+ (Dutton et al, 2013;Favero et al, 2018;Hedrich et al, 2014;Rubinstein et al, 2015a;Tai et al, 2014).…”

Section: Effects Of Scn1a Mutations On Neuronal Firingmentioning

confidence: 99%

Interneuron dysfunction in a new knock-in mouse model of SCN1A GEFS+

Zhu

Xie

et al. 2019

Preprint

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Advances in genome sequencing have identified over 1300 mutations in the SCN1A sodium channel gene that result in genetic epilepsies. However, how individual mutations within SCN1A produce seizures remains elusive for most mutations. Previous work from our lab has shown that the K1270T (KT) mutation, which is linked to GEFS+ (Genetic Epilepsy with Febrile Seizure plus) in humans, causes reduced firing of GABAergic neurons in a Drosophila knock-in model. To examine the effect of this mutation in mammals, we introduced the equivalent KT mutation into the mouse Scn1a (Scn1a KT ) gene using CRISPR/Cas9. Mouse lines carrying this mutation were examined in two widely used genetic backgrounds, C57BL/6NJ and 129X1/SvJ. In both backgrounds, homozygous mutants had spontaneous seizures and died by postnatal day 23. There was no difference in the lifespan of mice heterozygous for the mutation in either background when compared to wild-type littermates up to 6 months. Heterozygous mutants had heat-induced seizures at ~42 deg. Celsius, a temperature that did not induce seizures in wild-type littermates. In acute hippocampal slices, current-clamp recordings revealed a significant depolarized shift in action potential threshold and reduced action potential amplitude in parvalbumin-expressing inhibitory interneurons in Scn1a KT/+ mice. There was no change in the firing properties of excitatory CA1 pyramidal neurons. Our results indicate that Scn1a KT/+ mice develop seizures, and impaired action potential firing of inhibitory interneurons in Scn1a KT/+ mice may produce hyperexcitability in the hippocampus.

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Action Potential Initiation in Neocortical Inhibitory Interneurons

Abstract: Sodium channels add variety to inhibitory interneurons Different populations of inhibitory interneurons in the cerebral cortex express distinct subtypes of sodium channels, resulting in diverse action potential thresholds and network excitability.

Cited by 112 publications

References 60 publications

Opposing Effects on Na V 1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures

Opposing Effects on Na V 1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures

Functional implications of axon initial segment cytoskeletal disruption in stroke

Interneuron dysfunction in a new knock-in mouse model of SCN1A GEFS+

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