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The Journal of Neuroscience, April 1, 2001, 21(7):2343-2360

GABA Expression Dominates Neuronal Lineage Progression in the Embryonic Rat Neocortex and Facilitates Neurite Outgrowth via GABA_A Autoreceptor/Cl Channels

Dragan Maric¹, Qi-Ying Liu¹, Irina Maric¹, Sabeen Chaudry¹, Yoong-Hee Chang¹, Susan V. Smith¹, Werner Sieghart², Jean-Marc Fritschy³, and Jeffery L. Barker¹

¹ Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, ² Department of Biochemical Psychiatry, University Clinic for Psychiatry, A-1090 Vienna, Austria, and ³ Institute of Pharmacology, University of Zurich, CH-8057 Zurich, Switzerland

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 411 to 3323 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 Ca²⁺ (Ca²⁺_c) levels via Ca²⁺ entry through L-type Ca²⁺ channels. Block of this autocrine circuit at the level of GABA synthesis, GABA_A receptor activation, intracellular Cl ion homeostasis, or L-type Ca²⁺ 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 Ca²⁺_c. These results reveal a morphogenic role for GABA during embryonic neocortical neuron development that involves GABA_A autoreceptors and L-type Ca²⁺ channels.

Key words: embryonic; rat; development; cortical; neuritogenesis; GABA; GAD; FACS

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2172343-18$05.00/0

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