Protracted Developmental Trajectories of GABAA Receptor α1 and α2 Subunit Expression in Primate Prefrontal Cortex

Background: In schizophrenia, working memory dysfunction is associated with altered expression of gamma-aminobutyric acid (GABA)(A) receptor alpha 1 and alpha 2 subunits in the dorsolateral prefrontal cortex (DLPFC). In rodents, cortical alpha subunit expression shifts from low alpha 1 and high alpha 2 to high alpha 1 and low alpha 2 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 alpha 1 and alpha 2 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 alpha 1 and alpha 2 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 alpha 1 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 alpha 1 and alpha 2 subunits progressively increased and decreased, respectively, throughout postnatal development including adolescence. Furthermore, as predicted by the different functional properties of alpha 1-containing versus alpha 2-containing GABAA 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 a 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.