Feature Finding Title
Featured Finding Figure

In schizophrenia, working memory dysfunction is associated with altered expression of GABAA receptor α1 and α2 subunits in the dorsolateral prefrontal cortex (DLPFC).  In rodents, cortical α subunit expression shifts from low α1 and high α2 to high α1 and low α2 during early postnatal development.  Because these two α subunits confer different functional properties to the GABAA receptors containing them, we determined whether this shift in α1 and α2 subunit expression continues through adolescence in the primate DLPFC, potentially contributing to the maturation of working memory during this developmental period.  Levels of GABAA receptor α1 and α2 subunit mRNAs were determined in the DLPFC of 1 week, 4 week, 3 month, 15-17 month (pre-pubertal), 43-47 month (post-pubertal), and adult monkeys using in situ hybridization, followed by the quantification of α1 subunit protein by western blotting.  We also performed whole-cell patch clamp recording of miniature inhibitory post-synaptic potentials (mIPSPs) in DLPFC slices prepared from pre- and post-pubertal monkeys.  The mRNA and protein levels of α1 and α2 subunits, progressively increased and decreased, respectively, throughout postnatal development including adolescence; the timing of these shifts in expression differed by cortical layer (Figure).  Furthermore, as predicated by the different functional properties of α1-containing versus α2-containing GABAA receptors, the mIPSP duration was significantly shorter in post-pubertal than in pre-pubertal animals.  In contrast to rodents, the developmental shift in GABAA receptor α 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.

Hashimoto T, Nguyen QL, Rotaru D, Keenan T, Arion D, Beneyto M, Gonzalez-Burgos G, and Lewis DA: Protracted developmental trajectories of GABAA receptor α1 and α2 subunit expression in primate prefrontal cortex. Biol Psychiatry 65: 1015-1023, 2009.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
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