DISC1 Regulates GABAA Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons [Signal Transduction]

September 30th, 2015 by Wei, J., Graziane, N. M., Gu, Z., Yan, Z.

Association studies have suggested that DISC1 (Disrupted-in-Schizophrenia-1) confers a genetic risk at the level of endophenotypes that underlies many major mental disorders. Despite the progress on understanding the significance of DISC1 at neural development, the mechanisms underlying DISC1 regulation of synaptic functions remain elusive. Since 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. We found that cellular knockdown of DISC1 significantly reduced GABAAR-mediated synaptic and whole-cell current, while overexpression of wild-type DISC1, but not the C-terminal-truncated DISC1 (a schizophrenia-related mutant), significantly increased GABAAR currents in pyramidal neurons of 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 impact on GABAergic inhibitory transmission by regulating KIF5/microtubule-based GABAAR trafficking in the cortex. Knowledge gained from this study would shed light on how DISC1 and the GABA system are mechanistically linked and how their interactions are critical for maintaining a normal mental state.