GABA as a trophic factor for developing monoamine neurons

GABA exerts a variety of trophic influences on developing brain cells, as reviewed in this issue. During early stages of brain development, GABAergic axons course through regions where other neurotransmitter phenotypes are being generated. This raises the question of whether GABA may influence the ontogeny of these neurotransmitter systems in the embryonic brain. The brainstem provides a good example of this relationship, since GABAergic axons pass through the anlage of the developing raphe nuclei when serotonergic (5-HT) neurons are just beginning to differentiate and migrate away from the ventricular zone. Evidence that GABA regulates development of these and adjacent noradrenergic neurons has recently been obtained using embryonic brainstem cultures, which contain differentiating 5-HT, tyrosine hydroxylase (TH), and GABA neurons. These cultures also express multiple GABAA-receptor subunits that form functional GABAA/Cl- channels. GABAA receptor ligands produce differential effects on survival and growth of monoamine (5-HT, TH) and GABA neurons, and on expression of GABAA subunits in these cultures. These findings provide evidence that GABA can selectively regulate development of neurons of different neurotransmitter phenotypes, as well as developmental expression of its own receptors, and suggest that in utero exposure to GABAA receptor ligands could produce imbalances in monoaminergic versus GABAergic neurotransmission in the developing brain. Dieldrin, an organochlorine pesticide that acts as a GABAA antagonist, has potent effects on survival, and neurite outgrowth by 5-HT neurons, and GABAA subunit expression in brainstem cultures. Thus, maternal exposure to organochlorine pesticides could pose a risk to fetal brain development, especially during the first trimester of pregnancy.