Expression of distinct α subunits of GABAA receptor regulates inhibitory synaptic strength
Expression of distinct α subunits of GABAA receptor regulates inhibitory synaptic strength
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DOI：
10.1152/jn.00243.2004
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发表时间：
2004-09-01
影响因子：
2.5
通讯作者：
Vicini, S
中科院分区：
文献类型：
--
作者：
Ortinski, PI;Lu, CY;Vicini, S
GABA（A）受体分子组装中不同的α亚单位亚型是抑制性突触的功能特性及其由一系列药理学试剂调节的关键决定因素。我们研究了这些亚基对野生型和α 1亚基-/-小鼠原代培养物中小脑颗粒神经元抑制性突触发育变化的贡献。微型抑制性突触后电流（mIPSC）的衰减时间在体外6天（DIV 6）和DIV 12之间减半。这是由α 2和α 3亚基的减少，α 1和α 6亚基在突触表达的增加，以及选择性α亚基调节剂的作用的变化所证实的。随着来自-/-小鼠的细胞的发育，观察到mIPSC的小但显著的缩短以及α 3亚基表达的降低。相比之下，在DIV 11 -12时，-/-细胞中抑制性突触处α 2亚基的表达显著高于+/+细胞。未检测到α 5亚基，对选择性α 4/α 6亚基激动剂的敏感性增加表明-/-小鼠中突触外受体的表达增加。β 2/β 3亚基表达和洛瑞唑敏感性在+/+细胞中随着发育而增加，但在-/-细胞中不增加，支持α 1与β 2亚基的优先结合。突触电荷转移随着发育强烈下降，但在DIV 11 -12之前，+/+和-/-组中的细胞之间没有差异。我们的研究结果揭示了一种模式的顺序表达的α亚基的变化的功能功效的GABA能网络与发展。
Distinct alpha subunit subtypes in the molecular assembly of GABA(A) receptors are a critical determinant of the functional properties of inhibitory synapses and their modulation by a range of pharmacological agents. We investigated the contribution of these subunits to the developmental changes of inhibitory synapses in cerebellar granule neurons in primary cultures from wild-type and alpha1 subunit -/- mice. The decay time of miniature inhibitory postsynaptic currents (mIPSCs) halved between 6 days in vitro (DIV6) and DIV12. This was paralleled by the decrease of alpha2 and alpha3 subunits, the increase of alpha1 and alpha6 subunits expression at synapses, and changes in the action of selective alpha subunit modulators. A small but significant shortening of mIPSCs was observed with development in cells from -/- mice together with a decrease in the expression of alpha3 subunit. In contrast, the expression of alpha2 subunit at inhibitory synapses in -/- cells was significantly higher than in +/+ cells at DIV11-12. alpha5 subunit was not detected, and increased sensitivity to a selective alpha4/alpha6 subunit agonist suggests increased expression of extrasynaptic receptors in -/- mice. beta2/beta3 subunit expression and loreclezole sensitivity increased with development in +/+ but not in -/- cells, supporting the preferential association of the alpha1 with the beta2 subunit. Synaptic charge transfer strongly decreased with development but was not different between cells in the +/+ and -/- groups until DIV11-12. Our results uncover a pattern of sequential expression of alpha subunits underlying the changes in functional efficacy of GABAergic networks with development.