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Neuropsychopharmacology. 2014 Feb;39(3):528-37. doi: 10.1038/npp.2013.190. Epub 2013 Aug 6.

N-Glycosylation of GABAA receptor subunits is altered in Schizophrenia.

Author information

1
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
2
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.

Abstract

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 α1, β1, and β2 γ-aminobutyric type A receptor (GABAAR) subunits using deglycosylation protein shift assays. This was confirmed with lectin affinity assays that revealed glycan attachment on the α1, α4, and β1-3 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 α1 subunit, more immature N-glycosylation of the 49-kDa β1 subunit isoform, and altered total N-glycosylation of the β2 GABAAR subunit in schizophrenia. Measures of altered N-glycosylation of the β1 and β2 subunits were confounded by an increased apparent molecular mass of all β1 and β2 subunit isoforms in schizophrenia. Although N-glycosylation of α1, β1, and β2 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.

PMID:
23917429
PMCID:
PMC3895232
DOI:
10.1038/npp.2013.190
[Indexed for MEDLINE]
Free PMC Article
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