ALTERED EXPRESSION OF GAMMA(2L) AND GAMMA(2S) GABA(A) RECEPTOR SUBUNITS IN THE AGING RAT-BRAIN

Aging-related alterations in both protein and mRNA expression of gamma (2S) and gamma(2L) subunits of the GABA(A) receptors have been observe d in several brain areas of Sprague-Dawley and Fischer 344 rats. Subun it-specific antibodies to gamma(2S) and gamma(2L) as well as a ribopro be to the large intracellular loop of gamma(2), which recognizes both gamma(2S) and gamma(2L) mRNAs, in conjunction with computerized image analysis were used for quantitative immunocytochemistry and in situ hy bridization. In addition, specific oligonucleotide probes to gamma(2S) or gamma(2L) mRNA were used for quantitative dot blot hybridization. A large increase in the number of heavily immunostained neurons with t he anti-gamma(2L) antibody was detected in the cerebral cortex (115%) of old rats. However, only a small (but significant) aging-related inc rease in the density of gamma(2L) immunostaining (7%) was observed thr oughout the cerebral cortex whereas no significant aging-related chang e in gamma(2L) mRNA was detected in this brain region. Contrary to gam ma(2L) the gamma(2S) immunostaining did not show aging-related increas ed number of heavily immunostained neurons in cerebral cortex. Moreove r, the density of gamma(2S) immunostaining and the expression of gamma (2S) mRNA were significantly decreased in the cerebral cortex (9-24%). Important aging-related changes were also found in the cerebellum of old rats where the expression of both gamma(2L) and gamma(2S) peptides was significantly decreased (24% and 23% respectively). This decrease in gamma(2) protein expression was accompanied by decreased expressio n of gamma(2S) (16-38%) and gamma(2L) (24%) mRNAs. Nevertheless, the m ost important decrease of gamma(2S) (48%) and gamma(2L) protein (20%) was revealed in the molecular layer of the cerebellum. In addition, th e expression of gamma(2S) protein was increased (14%) whereas the expr ession of gamma(2L) was decreased (13%) in the granule cell layer. The refore, the relative expression of gamma(2S) protein in both layers wa s reversed in old animals. The observed aging-related changes in the e xpression of GABA(A) receptor subunits might lead to altered GABA(A) r eceptor/benzodiazepine receptor subunit composition.