EXCITATORY NEUROTRANSMISSION AND SEXUAL-DIFFERENTIATION OF THE BRAIN

During normal development there is a perinatal sensitive period during which the male brain is exposed to high levels of gonadal steroids, r esulting in permanent differentiation of neural substrates. The cellul ar mechanisms mediating hormonally induced sexual differentiation rema in largely unknown, In the adult brain, steroids exert profound influe nces on the amino acid transmitters, GABA, and glutamate. We have foun d steroid regulation of amino acid neurotransmission during the perina tal sensitive period and propose this may be functionally related to s exual differentiation of the brain, Specifically, the mRNA coding for the rate-limiting enzyme in GABA synthesis, glutamic acid decarboxylas e (GAD), is up to twice as high in some steroid-concentrating regions of the neonatal male brain compared to females, including the arcuate nucleus, dorsomedial nucleus, and the CA1 region of hippocampus. Sex d ifferences in GABA tissue concentrations positively correlate with GAD mRNA differences in several brain regions. There are also sex differe nces in protein levels of GABA(A) receptor subunits, In parallel with these findings are significantly higher levels of binding to the non-N MDA glutamate receptor in steroid-concentrating regions of male brain. Given that GABA is an inhibitory transmitter and glutamate is an exci tatory amino acid, these results initially appear paradoxical, However , in contrast to its inhibitory action in the adult brain, early in de velopment GABA is actually excitatory and acts in a manner analogous t o glutamate, Therefore, the combination of increased excitatory GABAer gic and glutamatergic activity should result in substantially higher l evels of neuronal excitation in the male brain, We speculate that an i ncreased level of neuronal excitation is a potential mechanism mediati ng the permanent masculinization of the brain. (C) 1997 Elsevier Scien ce Inc.