title: DISC1 Protein Regulates γ-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons.
abstract: Association studies have suggested that Disrupted-in-Schizophrenia 1 (DISC1) confers a genetic risk at the level of endophenotypes that underlies many major mental disorders. Despite the progress in understanding the significance of DISC1 at neural development, the mechanisms underlying DISC1 regulation of synaptic functions remain elusive. Because alterations in the cortical GABA system have been strongly linked to the pathophysiology of schizophrenia, one potential target of DISC1 that is critically involved in the regulation of cognition and emotion is the GABAA receptor (GABAAR). We found that cellular knockdown of DISC1 significantly reduced GABAAR-mediated synaptic and whole-cell current, whereas overexpression of wild-type DISC1, but not the C-terminal-truncated DISC1 (a schizophrenia-related mutant), significantly increased GABAAR currents in pyramidal neurons of the prefrontal cortex. These effects were accompanied by DISC1-induced changes in surface GABAAR expression. Moreover, the regulation of GABAARs by DISC1 knockdown or overexpression depends on the microtubule motor protein kinesin 1 (KIF5). Our results suggest that DISC1 exerts an important effect on GABAergic inhibitory transmission by regulating KIF5/microtubule-based GABAAR trafficking in the cortex. The knowledge gained from this study would shed light on how DISC1 and the GABA system are linked mechanistically and how their interactions are critical for maintaining a normal mental state.
authors.affiliation: From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214 and the Veterans Affairs Western New York Healthcare System, Buffalo, New York 14215.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214 and.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Graziane
authors.affiliation: From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214 and.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Gu
authors.affiliation: From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214 and the Veterans Affairs Western New York Healthcare System, Buffalo, New York 14215 zhenyan@buffalo.edu.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003071:Cognition / Q000502:physiology; D004644:Emotions / Q000502:physiology; D055785:Gene Knockdown Techniques; D016547:Kinesins / Q000378:metabolism; D008606:Mental Processes / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics; D009435:Synaptic Transmission
chemical_list: C498795:Disc1 protein, rat; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A; C547919:Kif5A protein, rat; D016547:Kinesins
keywords: GABA receptor; electrophysiology; intracellular trafficking; schizophrenia; synapse