GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA(A) autoreceptor/Cl- channels

GABA emerges as a trophic signal during rat neocortical development in whic h it modulates proliferation of neuronal progenitors in the ventricular/sub ventricular zone (VZ/SVZ) and mediates radial migration of neurons from the VZ/VZ to the cortical plate/subplate (CP/SP) region. In this study we inve stigated the role of GABA in the earliest phases of neuronal differentiatio n in the CP/SP. GABAergic-signaling components emerging during neuronal lin eage progression were comprehensively characterized using flow cytometry an d immunophenotyping together with physiological indicator dyes. During migr ation from the VZ/SVZ to the CP/SP, differentiating cortical neurons became predominantly GABAergic, and their dominant GABA(A) receptor subunit expre ssion pattern changed from alpha4 beta1 gamma1 to alpha3 beta3 gamma2 gamma 3 coincident with an increasing potency of GABA on GABA(A) receptor-mediate d depolarization. GABA(A) autoreceptor/Cl- channel activity in cultured CP/ SP neurons dominated their baseline potential and indirectly their cytosoli c Ca2+ (Ca-c(2+)) 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 att enuated neurite outgrowth in most GABAergic CP/SP neurons. In the absence o f autocrine GABAergic signaling, neuritogenesis could be preserved by depol arizing cells and elevating Ca-c(2+). These results reveal a morphogenic ro le for GABA during embryonic neocortical neuron development that involves G ABA, autoreceptors and L-type Ca2+ channels.