Department of Medical Physiology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
Faculty of Health and Medical Care, Saitama Medical University, Hidaka, Saitama, Japan.
J Neurochem. 2021 Mar;156(5):604-613. doi: 10.1111/jnc.15159. Epub 2020 Sep 27.
De novo heterozygous mutations in the STX1B gene, encoding syntaxin 1B, cause a familial, fever-associated epilepsy syndrome. Syntaxin 1B is an essential component of the pre-synaptic neurotransmitter release machinery as a soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein that regulates the exocytosis of synaptic vesicles. It is also involved in regulating the functions of the SLC6 family of neurotransmitter transporters that reuptake neurotransmitters, including inhibitory neurotransmitters, such as γ-aminobutyric acid (GABA) and glycine. The purpose of the present study was to elucidate the molecular mechanisms underlying the development of febrile seizures by examining the effects of syntaxin 1B haploinsufficiency on inhibitory synaptic transmission during hyperthermia in a mouse model. Stx1b gene heterozygous knockout (Stx1b ) mice showed increased susceptibility to febrile seizures and drug-induced seizures. In cultured hippocampal neurons, we examined the temperature-dependent properties of neurotransmitter release and reuptake by GABA transporter-1 (GAT-1) at GABAergic neurons using whole-cell patch-clamp recordings. The rate of spontaneous quantal GABA release was reduced in Stx1b mice. The hyperthermic temperature increased the tonic GABA current in wild-type (WT) synapses, but not in Stx1b synapses. In WT neurons, recurrent bursting activities were reduced in a GABA-dependent manner at hyperthermic temperature; however, this was abolished in Stx1b neurons. The blockade of GAT-1 increased the tonic GABA current and suppressed recurrent bursting activities in Stx1b neurons at the hyperthermic temperature. These data suggest that functional abnormalities associated with GABA release and reuptake in the pre-synaptic terminals of GABAergic neurons may increase the excitability of the neural circuit with hyperthermia.
STX1B 基因（编码突触融合蛋白 1B）中的从头杂合突变导致家族性发热相关癫痫综合征。突触融合蛋白 1B 是突触前神经递质释放机制的重要组成部分，作为可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体蛋白，调节突触小泡的胞吐作用。它还参与调节 SLC6 家族神经递质转运体的功能，这些转运体再摄取神经递质，包括抑制性神经递质，如γ-氨基丁酸（GABA）和甘氨酸。本研究旨在通过检查语法 1B 单倍不足对高热时抑制性突触传递的影响，阐明发热性惊厥发展的分子机制，建立在一个小鼠模型。Stx1b 基因杂合敲除（Stx1b ）小鼠表现出对发热性惊厥和药物诱导性惊厥的易感性增加。在培养的海马神经元中，我们使用全细胞膜片钳记录法在 GABA 能神经元中检查了 GABA 转运体-1（GAT-1）介导的神经递质释放和再摄取的温度依赖性特性。Stx1b 小鼠中自发性量子 GABA 释放的速率降低。在野生型（WT）突触中，高热温度增加了紧张性 GABA 电流，但在 Stx1b 突触中没有增加。在 WT 神经元中，在高热温度下，GABA 依赖性地减少了反复爆发活动；然而，在 Stx1b 神经元中，这种作用被消除。在高热温度下，GAT-1 的阻断增加了 Stx1b 神经元中的紧张性 GABA 电流，并抑制了反复爆发活动。这些数据表明，GABA 能神经元突触前末梢中与 GABA 释放和再摄取相关的功能异常可能会增加高热时神经回路的兴奋性。
