BACKGROUND: In schizophrenia, working memory dysfunction is associated with altered expression of gamma-aminobutyric acid (GABA)(A) receptor alpha1 and alpha2 subunits in the dorsolateral prefrontal cortex (DLPFC). In rodents, cortical alpha subunit expression shifts from low alpha1 and high alpha2 to high alpha1 and low alpha2 during early postnatal development. Because these two alpha subunits confer different functional properties to the GABA(A) receptors containing them, we determined whether this shift in alpha1 and alpha2 subunit expression continues through adolescence in the primate DLPFC, potentially contributing to the maturation of working memory during this developmental period.
METHODS: Levels of GABA(A) receptor alpha1 and alpha2 subunit mRNAs were determined in the DLPFC of monkeys aged 1 week, 4 weeks, 3 months, 15-17 months (prepubertal), and 43-47 months (postpubertal) and in adult monkeys using in situ hybridization, followed by the quantification of alpha1 subunit protein by western blotting. We also performed whole-cell patch clamp recording of miniature inhibitory postsynaptic potentials (mIPSPs) in DLPFC slices prepared from pre- and postpubertal monkeys.
RESULTS: The mRNA and protein levels of alpha1 and alpha2 subunits progressively increased and decreased, respectively, throughout postnatal development including adolescence. Furthermore, as predicted by the different functional properties of alpha1-containing versus alpha2-containing GABA(A) receptors, the mIPSP duration was significantly shorter in postpubertal than in prepubertal animals.
CONCLUSIONS: In contrast to rodents, the developmental shift in GABA(A) receptor alpha subunit expression continues through adolescence in primate DLPFC, inducing a marked change in the kinetics of GABA neurotransmission. Disturbances in this shift might underlie impaired working memory in schizophrenia.