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Volume 17, Number 7, Issue of April 1, 1997 pp. 2420-2428
Copyright ©1997 Society for Neuroscience

GABA_A Receptors Mediate Trophic Effects of GABA on Embryonic Brainstem Monoamine Neurons In Vitro

Received Dec. 23, 1996; accepted Jan. 13, 1997.

Jiangping Liu¹, A. Leslie Morrow², Leslie Devaud², Dennis R. Grayson³, and Jean M. Lauder¹

Departments of ¹ Cell Biology and Anatomy and ² Psychiatry and Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, and ³ Department of Psychiatry, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212

The inhibitory neurotransmitter GABA may act as a trophic signal for developing monoamine neurons in embryonic rat brain, because GABA neurons and their receptors appear in brainstem during generation of monoamine neurons. To test this hypothesis, we used dissociated cell cultures from embryonic day 14 rat brainstem, which contains developing serotonin (5-HT), noradrenaline (tyrosine hydroxylase; TH), and GABA neurons. Immunocytochemistry and reverse transcription-PCR (RT-PCR) revealed the presence of multiple , , , and  subunits in these cultures. Competitive RT-PCR demonstrated high levels of 3 subunit transcripts. Expression of functional GABA_A receptors was demonstrated using ³⁶Cl flux assays. To investigate GABAergic regulation of neuronal survival and growth, cultures were treated for 1-3 d in vitro with 10 µM GABA and/or GABA_A antagonist (bicuculline or the pesticide dieldrin). The effects of treatments were quantified by analysis of immunoreactive 5-HT, TH, and GABA neurons. GABA_A receptor ligands differentially regulated neuronal survival and growth depending on neurotransmitter phenotype. GABA exerted positive effects on monoamine neurons, which were countered by bicuculline (and dieldrin, 5-HT neurons only). By itself, bicuculline produced inhibitory effects on both 5-HT and TH neurons, whereas dieldrin potently inhibited 5-HT neurons only. GABA neurons responded positively to both antagonists, but more strongly to bicuculline. Taken together, these results demonstrate that the activation/inhibition of GABA_A receptors produces opposite effects on the development of embryonic monoamine and GABA neurons. This suggests that these neurotransmitter phenotypes may express GABA_A receptors that differ in fundamental ways, and these differences determine the developmental responses of these cells to GABAergic stimuli.

Key words: GABA_A receptor; 5-HT; tyrosine hydroxylase; survival; neurite outgrowth; rat; bicuculline; organochlorine pesticides; dieldrin; RT-PCR; chloride influx; embryonic; brainstem

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