Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain

Inhibitory neurotransmission is primarily mediated by nu-aminobutyric acid (GABA) activating synaptic GABA type A receptors (GABA(A)R). In schizophrenia, presynaptic GABAergic signaling deficits are among the most replicated findings; however, postsynaptic GABAergic deficits are less well characterized. Our lab has previously demonstrated that although there is no difference in total protein expression of the alpha 1-6, beta 1-3 or nu 2 GABA(A)R subunits in the superior temporal gyrus (STG) in schizophrenia, the alpha 1, beta 1 and beta 2 GABA(A)R subunits are abnormally N-glycosylated. N-glycosylation is a posttranslational modification that has important functional roles in protein folding, multimer assembly and forward trafficking. To investigate the impact that altered N-glycosylation has on the assembly and trafficking of GABA(A)Rs in schizophrenia, this study used western blot analysis to measure the expression of alpha 1, alpha 2, beta 1, beta 2 and nu 2 GABA(A)R subunits in subcellular fractions enriched for endoplasmic reticulum (ER) and synapses (SYN) from STG of schizophrenia (N = 16) and comparison (N = 14) subjects and found evidence of abnormal localization of the beta 1 and beta 2 GABA(A)R subunits and subunit isoforms in schizophrenia. The beta 2 subunit is expressed as three isoforms at 52 kDa (beta 2(52) (kDa)), 50 kDa (beta 2(50) (kDa)) and 48 kDa (beta 2(48 kDa)). In the ER, we found increased total beta 2 GABA(A)R subunit (beta 2(ALL)) expression driven by increased beta 2(50) (kDa), a decreased ratio of beta 2(48 kDa):beta 2(ALL) and an increased ratio of beta 2(50) (kDa):beta 2(48) (kDa.) Decreased ratios of beta 1:beta 2(ALL) and beta 1:beta 2(50 kDa) in both the ER and SYN fractions and an increased ratio of beta 2(52) (kDa):beta 2(48 kDa) at the synapse were also identified in schizophrenia. Taken together, these findings provide evidence that alterations of N-glycosylation may contribute to GABAergic signaling deficits in schizophrenia by disrupting the assembly and trafficking of GABA(A)Rs.