Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a+/\u2212 mouse model of Dravet syndrome

Kouya Uchino,Yuna Adaniya,Hiroyuki Kawano,Yasuyoshi Tanaka,Shutaro Katsurabayashi,Masanobu Deshimaru,Takuya Watanabe,Kaori Kubota,Ai Asahara,Katsunori Iwasaki,Shinichi Hirose

doi:10.1038/s41598-021-90224-4

Abstract

Dravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. More than 80% of all patients have a heterozygous abnormality in the SCN1A gene, which encodes a subunit of Na+ channels in the brain. However, the detailed pathogenesis of DS remains unclear. This study investigated the synaptic pathogenesis of this disease in terms of excitatory/inhibitory balance using a mouse model of DS. We show that excitatory postsynaptic currents were similar between Scn1a knock-in neurons (Scn1a+/− neurons) and wild-type neurons, but inhibitory postsynaptic currents were significantly lower in Scn1a+/− neurons. Moreover, both the vesicular release probability and the number of inhibitory synapses were significantly lower in Scn1a+/− neurons compared with wild-type neurons. There was no proportional increase in inhibitory postsynaptic current amplitude in response to increased extracellular Ca2+ concentrations. Our study revealed that the number of inhibitory synapses is significantly reduced in Scn1a+/− neurons, while the sensitivity of inhibitory synapses to extracellular Ca2+ concentrations is markedly increased. These data suggest that Ca2+ tethering in inhibitory nerve terminals may be disturbed following the synaptic burst, likely leading to epileptic symptoms.

Highlights

Dravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy
We did not observe any enhancement of excitatory synaptic transmission at the single-neuron level in Scn1a+/− neurons
Inhibitory synaptic transmission was significantly lower in Scn1a+/− neurons than in WT neurons

Summary

Introduction

Dravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. Our study revealed that the number of inhibitory synapses is significantly reduced in Scn1a+/− neurons, while the sensitivity of inhibitory synapses to extracellular Ca2+ concentrations is markedly increased. Heterozygous mutations in SCN1A, the gene encoding Nav1.1 (the α subunit of voltage-gated Na+ channels), have been identified in more than 80% of patients with DS. It remains unclear how this gene mutation causes intractable epilepsy. The common mechanism of these aforementioned studies was that SCN1A mutations result in a loss of inhibitory neural function This underlying mechanism indicates that excitatory neural function is increased in the brain, making it highly susceptible to epilepsy because of the suppression of inhibitory neural function in the central nervous network. Understanding epilepsy as a “synaptic pathology” and elucidating synaptic recovery mechanisms may help to develop fundamental epilepsy therapies and aid in drug discovery

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