N-Glycosylation of GABAA Receptor Subunits is Altered in Schizophrenia

The molecular mechanisms of schizophrenia have been under investigation for decades; however, the exact causes of this debilitating neuropsychiatric disorder are still unknown. Previous studies have identified multiple affected neurotransmitter systems, brain regions, and cell types, each making a unique contribution to symptom presentation and pathophysiology. Numerous studies have identified gene and protein expression changes in schizophrenia, but the role of post-translational modifications, specifically N-glycosylation, has only recently become a target of investigation. N-glycosylation of molecules associated with glutamatergic neurotransmission is disrupted in schizophrenia, but it was unknown if these alterations are exclusive to the glutamatergic system or due to a more generalized deficit. In normal human cortex, we found evidence for N-glycosylation of the alpha 1, alpha 1, and beta 2 gamma-aminobutyric type A receptor (GABAAR) subunits using deglycosylation protein shift assays. This was confirmed with lectin affinity assays that revealed glycan attachment on the alpha 1, alpha 4, and beta 1-3 GABAAR subunits. Examining GABAAR subunit N-glycosylation in matched pairs of schizophrenia (N 14) and comparison (N 14) of superior temporal gyrus revealed a smaller molecular mass of immature N-glycans on the alpha 1 subunit, more immature N-glycosylation of the 49-kDa beta 1 subunit isoform, and altered total N-glycosylation of the beta 2 GABAAR subunit in schizophrenia. Measures of altered N-glycosylation of the beta 1 and beta 2 subunits were confounded by an increased apparent molecular mass of all beta 1 and beta 2 subunit isoforms in schizophrenia. Although N-glycosylation of alpha 1, beta 1, and beta 2 were all changed in schizophrenia, the concentrations of GABAAR subunits themselves were unchanged. These findings suggest that disruptions of N-glycosylation in schizophrenia are not exclusive to glutamate and may indicate a potential disruption of a central cell signaling process in this disorder.