Maric D, Liu Q Y, Maric I, Chaudry S, Chang Y H, Smith S V, Sieghart W, Fritschy J M, Barker J L
Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosci. 2001 Apr 1;21(7):2343-60. doi: 10.1523/JNEUROSCI.21-07-02343.2001.
GABA emerges as a trophic signal during rat neocortical development in which it modulates proliferation of neuronal progenitors in the ventricular/subventricular zone (VZ/SVZ) and mediates radial migration of neurons from the VZ/SVZ to the cortical plate/subplate (CP/SP) region. In this study we investigated the role of GABA in the earliest phases of neuronal differentiation in the CP/SP. GABAergic-signaling components emerging during neuronal lineage progression were comprehensively characterized using flow cytometry and immunophenotyping together with physiological indicator dyes. During migration from the VZ/SVZ to the CP/SP, differentiating cortical neurons became predominantly GABAergic, and their dominant GABA(A) receptor subunit expression pattern changed from alpha4beta1gamma1 to alpha3beta3gamma2gamma3 coincident with an increasing potency of GABA on GABA(A) receptor-mediated depolarization. GABA(A) autoreceptor/Cl(-) channel activity in cultured CP/SP neurons dominated their baseline potential and indirectly their cytosolic Ca(2+) (Ca(2+)c) levels via Ca(2+) entry through L-type Ca(2+) channels. Block of this autocrine circuit at the level of GABA synthesis, GABA(A) receptor activation, intracellular Cl(-) ion homeostasis, or L-type Ca(2+) channels attenuated neurite outgrowth in most GABAergic CP/SP neurons. In the absence of autocrine GABAergic signaling, neuritogenesis could be preserved by depolarizing cells and elevating Ca(2+)c. These results reveal a morphogenic role for GABA during embryonic neocortical neuron development that involves GABA(A) autoreceptors and L-type Ca(2+) channels.
在大鼠新皮质发育过程中，γ-氨基丁酸（GABA）作为一种营养信号出现，它调节脑室下区/室管膜下区（VZ/SVZ）中神经祖细胞的增殖，并介导神经元从VZ/SVZ向皮质板/亚板（CP/SP）区域的放射状迁移。在本研究中，我们调查了GABA在CP/SP中神经元分化最早阶段的作用。利用流式细胞术、免疫表型分析以及生理指示剂染料，全面表征了神经谱系进展过程中出现的GABA能信号成分。在从VZ/SVZ迁移到CP/SP的过程中，正在分化的皮质神经元主要变成GABA能神经元，并且它们主要的GABA(A)受体亚基表达模式从α4β1γ1转变为α3β3γ2γ3，这与GABA对GABA(A)受体介导的去极化作用的增强相一致。培养的CP/SP神经元中的GABA(A)自身受体/Cl(-)通道活性主导了它们的基线电位，并通过L型Ca(2+)通道的Ca(2+)内流间接调节它们的胞质Ca(2+)（Ca(2+)c）水平。在GABA合成、GABA(A)受体激活、细胞内Cl(-)离子稳态或L型Ca(2+)通道水平阻断这种自分泌回路，会减弱大多数GABA能CP/SP神经元的神经突生长。在没有自分泌GABA能信号的情况下，通过使细胞去极化和提高Ca(2+)c可以保留神经突发生。这些结果揭示了GABA在胚胎新皮质神经元发育过程中的形态发生作用，这涉及GABA(A)自身受体和L型Ca(2+)通道。
