Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain

• Published in: Translational psychiatry Vol. 5; no. 8; p. e612
• Main Authors: Mueller, T M, Remedies, C E, Haroutunian, V, Meador-Woodruff, J H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.08.2015; Nature Publishing Group
• Subjects: 101/28; 631/378/340; 692/699/476/1799; 82; 82/29; 82/80; Aged; Behavioral Sciences; Biological Psychology; Blotting, Western; Brain - metabolism; Brain - physiopathology; Case-Control Studies; Endoplasmic Reticulum - chemistry; Female; Glycosylation; Humans; Male; Medicine; Medicine & Public Health; Neurosciences; Original; original-article; Pharmacotherapy; Psychiatry; Receptors, GABA-A - analysis; Receptors, GABA-A - metabolism; Receptors, GABA-A - physiology; Receptors, GABA-B - metabolism; Receptors, GABA-B - physiology; Schizophrenia - metabolism; Schizophrenia - physiopathology; Subcellular Fractions - chemistry; Synapses - chemistry; Temporal Lobe - chemistry
• DOI: 10.1038/tp.2015.102
• ISSN: 2158-3188

Inhibitory neurotransmission is primarily mediated by γ-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 α1–6, β1–3 or γ2 GABA A R subunits in the superior temporal gyrus (STG) in schizophrenia, the α1, β1 and β2 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 α1, α2, β1, β2 and γ2 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 β1 and β2 GABA A R subunits and subunit isoforms in schizophrenia. The β2 subunit is expressed as three isoforms at 52 kDa (β2 52 kDa ), 50 kDa (β2 50 kDa ) and 48 kDa (β2 48 kDa ). In the ER, we found increased total β2 GABA A R subunit (β2 ALL ) expression driven by increased β2 50 kDa , a decreased ratio of β2 48 kDa :β2 ALL and an increased ratio of β2 50 kDa :β2 48 kDa . Decreased ratios of β1:β2 ALL and β1:β2 50 kDa in both the ER and SYN fractions and an increased ratio of β2 52 kDa :β2 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.