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Developmental Regulation of inhibitory neuronal circuits by neural activity

神经活动对抑制性神经元回路的发育调节

基本信息

批准号：
11670044
负责人：
NABEKURA Junichi
金额：
$ 2.11万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

The regulatory mechanisms of intracellular Cl-concentration ([Cl-] i ) were investigated in the lateral superior olive (LSO) neurons of various developmental stages by taking advantage of gramicidin perforated patch recording mode which enables neuronal [Cl-] i measurement. Responses to glycine changed from depolarization to hyperpolarization during the second week after birth, resulting from [Cl-] i decrease. Furosemide equally altered the [Cl-] i of both immature and mature LSO neurons, indicating substantial contributions of furosemide-sensitive intracellular Cl- regulators ; i.e. K+-Cl- cotransporter (KCC) and Na+-K+-Cl- cotransporter (NKCC), throughout this early development. Increase of extracellular K+ concentration and replacement of intracellular K+ with Cs+ resulted in [Cl-] i elevation at postnatal day (P) 13-15, but not at P0-2, indicating that the mechanism of neuronal Cl- extrusion is sensitive to both furosemide and K+-gradient, and poorly developed in immature LSO neurons. In addition, removal of extracellular Na+ decreased [Cl-] i at P0-2, suggesting the existence of extracellular Na+- dependent and furosemide-sensitive Cl-accumulation in immature LSO neurons. These data show clearly that developmental changes of Cl--cotransporters alter [Cl-] i and are responsible for the switch from the neonatal Cl- efflux to the mature Cl- influx in LSO neurons. Such maturational changes in Cl--cotransporters might have the important functional roles for glycinergic and GABAergic synaptic transmission and the broader implications for LSO and auditory development.

利用短杆菌肽穿孔膜片记录技术，研究了不同发育阶段外侧上级橄榄核（LSO）神经元胞内Cl-浓度（[Cl-] i）的调节机制。甘氨酸的反应发生变化，从去极化超极化在出生后的第二周，导致[Cl-] i下降。呋塞米同样改变了未成熟和成熟LSO神经元的[Cl-] i，表明呋塞米敏感的细胞内Cl-调节剂，即K+-Cl-协同转运体（KCC）和Na+-K+-Cl-协同转运体（NKCC），在整个早期发育过程中的实质性贡献。细胞外K+浓度增加和Cs+置换细胞内K+导致[Cl-] i在出生后13-15天（P）升高，但在出生后0 -2天（P）不升高，表明神经元Cl-排出机制对速尿和K+梯度敏感，而在未成熟的LSO神经元中发育不良。此外，在P0-2去除细胞外Na+降低[Cl-] i，这表明在未成熟的LSO神经元中存在细胞外Na+依赖性和呋塞米敏感性Cl-积聚。这些数据清楚地表明，发展变化的Cl-协同转运改变[Cl-] i和负责开关从新生儿Cl-流出到成熟的Cl-流入LSO神经元。这种成熟的变化，Cl-cotransporters可能有重要的功能作用甘氨酸和GABA能突触传递和更广泛的影响LSO和听觉发展。