GABA Expression Dominates Neuronal Lineage Progression in the Embryonic Rat Neocortex and Facilitates Neurite Outgrowth via GABAAAutoreceptor/Cl−Channels
Journal of Neuroscience
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
... ed 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 ␣4␤1␥1 to ␣3␤3␥2␥3 coincident with an increasing potency of GABA on GABA A receptor-mediated depolarization. GABA A autoreceptor/Cl Ϫ channel activity in cultured CP/SP neurons dominated their baseline potential and indirectly their cytosolic Ca 2ϩ (Ca 2ϩ c ) levels via Ca 2ϩ entry through L-type Ca 2ϩ channels. Block of this autocrine circuit at the level of GABA synthesis, GABA A receptor activation, intracellular Cl Ϫ ion homeostasis, or L-type Ca 2ϩ 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 2ϩ c . These results reveal a morphogenic role for GABA during embryonic neocortical neuron development that involves GABA A autoreceptors and L-type Ca 2ϩ channels.