Mechanism of synapse elimination during circitogenesis of developing brain

发育中大脑循环发生过程中突触消除的机制

• 批准号: 14580773
• 负责人: KAWAI Yoshinori
• 金额: $ 2.18万
• 依托单位: JIKEI UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580773/
• 关键词: synapse elimination; GABA; GABAA-type receptor; nucleus tractus solitarius; development; neuronal circuit; subunit

gammna-aminobutyric acid (GABA) is a main inhibitory neurotransmitter in the central nervous system and thought to be critically involved in regulating excitatory neurotransmission. For the' inhibitory neurotransmission, GABA-A receptors, a pentameric hetero-oligomer ligand-gated chloride channel consisting mainly of alpha, beta and gamma subunits, must be clustered at the~postsynaptic membranes. In the present study, how GABAergic synaptic activity and expression of molecules responsible for the receptor-mediated transmission are regulated and correlated with each other during development, was addressed in the caudal nucleus of the tractus solitarius (NTS). GABAergic inhibitory postsynaptic currents (IPSCs) and expression of GABA-A receptor gamma1 subunit, which is reported to be essential for the receptor clustering at the postsynaptic membranes, were consistently evident in small-sized neurons of the caudal NTS during the early postnatal period (P1-6). After the first postnatal week, both IPSCs and expression of GABA-A receptor gamma 1 subunit virtually disappeared in these neurons. Low-level expression of GABAA receptor gamma2 subunit and gephyrin were consistently observed in the NTS. Electron microscopy revealed that number of GABAergic axosomatic synapses was drastically decreased during the development. Pharmacological properties of evoked GAI3A currents suggest a conversion of GABA-A receptor subunit configurations from alpha/beta/gamma to alpha/beta in small-sized neurons. These results show that GABAergic synaptic activity and gamma1 subunit expression were well correlated with each other and regulated developmentally in specific type of NTS neurons to establish the local neuronal networks of adult type. This phenomenon may underlie an establishment of cardiovascular and respiratory reflex circuits in the medulla.

γ-氨基丁酸（GABA）是中枢神经系统中的主要抑制性神经递质，并且被认为在调节兴奋性神经传递中起关键作用。GABA-A受体是一种五聚体异源寡聚体配体门控氯离子通道，主要由α、β和γ亚基组成，必须聚集在突触后膜上，才能抑制神经传递。在本研究中，GABA能突触活动和负责受体介导的传输的分子的表达是如何调节和相互关联的发展过程中，在孤束核（NTS）的尾侧核解决。GABA能抑制性突触后电流（IPSC）和GABA-A受体γ 1亚单位的表达在出生后早期（P1-6）在尾侧NTS的小尺寸神经元中一直是明显的，据报道GABA-A受体γ 1亚单位对于突触后膜上的受体聚集是必需的。出生后第一周，IPSC和GABA-A受体γ 1亚单位的表达几乎消失在这些神经元。NTS中GABAA受体γ 2亚基和桥蛋白的低水平表达一致。电镜观察发现，GABA能轴体突触的数量在发育过程中急剧减少。诱发的GAI 3A电流的药理学特性表明，在小尺寸神经元中，GABA-A受体亚单位构型从α/β/γ转化为α/β。这些结果表明，GABA能突触活动和γ 1亚基表达之间存在着良好的相关性，并在特定类型的NTS神经元中受到发育调节，从而建立起成人型的局部神经元网络。这种现象可能是延髓中心血管和呼吸反射回路建立的基础。

项目成果

Miyake S, Yamashita T, Taniguchi M, Tamatani M, Sato K, Kawai Y, Senba E, Mitsuda N, Hori O, Yamaguchi A, Tohyama M.: "Expression of mitochondrial tricarboxylate carrier TCC mRNA and protein in the rat brain."Brain Res Mol Brain Res. 100. 67-73 (2002)

Miyake S、Yamashita T、Taniguchi M、Tamatani M、Sato K、Kawai Y、Senba E、Mitsuda N、Hori O、Yamaguchi A、Tohyama M.：“线粒体三羧酸盐载体 TCC mRNA 和蛋白质在大鼠脑中的表达。”

Miyake S, Yamashita T, Taniguchi M, Tamatani M, Sato K, Kawai Y, Senba E, Mitsuda N, Hon 0, Yarn aguchi A, Tohyama M.: "Expression of mitochondrial tricarboxylate carrier TCC mRNA and protein in the rat brain."Brain Res Mol Brain Res. 100. 67-73 (2002)

Miyake S、Yamashita T、Taniguchi M、Tamatani M、Sato K、Kawai Y、Senba E、Mitsuda N、Hon 0、Yarn aguchi A、Tohyama M.：“线粒体三羧酸盐载体 TCC mRNA 和蛋白质在大鼠脑中的表达。