Heterogeneity of hippocampal GABA(A) receptors: Regulation by corticosterone

Chronic stressors produce changes in hippocampal neurochemistry, neuronal m orphology, and hippocampal-dependent learning and memory processes. In rats , stress-induced changes in CA3 apical dendritic structure are mediated by corticosterone (CORT) acting, in part, on excitatory amino acid neurotransm ission. CORT also alters GABA-mediated inhibitory neurotransmission, so the GABA(A) receptor system may also contribute to dendritic remodeling and ot her stress-related changes in hippocampal function. A previous study indica ted that chronic CORT treatment produces complex changes in GABA(A) recepto r subunit mRNA levels, so we hypothesized that CORT alters the pharmacologi cal properties of hippocampal GABA(A) receptors. To test this, adult male r ats were treated with CORT or vehicle pellets for 10 d, after which we quan tified [S-35]t-butylbicyclophosphorothionate ([S-35]TBPS) and [H-3]flunitra zepam binding to GABA(A) receptors using in vitro receptor autoradiography. Pharmacological properties of receptors were assessed by examining the all osteric regulation of binding at both sites by GABA and 5 alpha -pregnane-3 alpha, 21-diol-20-one (THDOC), an endogenous anxiolytic steroid. We found striking regional differences in the modulation of [S-35]TBPS binding, part icularly between strata radiatum and strata oriens, suggesting a functional heterogeneity among hippocampal GABA(A) receptors even within the apical v ersus basal dendrites of pyramidal neurons. Furthermore, we found that CORT treatment decreased the negative modulation of hippocampal [S-35]TBPS bind ing by both GABA and THDOC and increased the enhancement of [H-3]flunitraze pam binding by GABA and THDOC in the dentate gyrus. Together, these data su ggest that prolonged exposure to stress levels of corticosteroids may alter hippocampal inhibitory tone by regulating the pharmacological properties o f GABA(A) receptors in discrete dendritic subfields.