RT Journal Article SR Electronic T1 DISC1 regulates N-Methyl-D-Aspartate receptor dynamics: Abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness JF bioRxiv FD Cold Spring Harbor Laboratory SP 349365 DO 10.1101/349365 A1 Elise L.V. Malavasi A1 Kyriakos D. Economides A1 Ellen Grünewald A1 Paraskevi Makedonopoulou A1 Philippe Gautier A1 Shaun Mackie A1 Laura C. Murphy A1 Hannah Murdoch A1 Darragh Crummie A1 Fumiaki Ogawa A1 Daniel L. McCartney A1 Shane T. O’Sullivan A1 Karen Burr A1 Helen S. Torrance A1 Jonathan Phillips A1 Marion Bonneau A1 Susan M. Anderson A1 Paul Perry A1 Matthew Pearson A1 Costas Constantinides A1 Hazel Davidson-Smith A1 Mostafa Kabiri A1 Barbara Duff A1 Mandy Johnstone A1 H. Greg Polites A1 Stephen Lawrie A1 Douglas Blackwood A1 Colin A. Semple A1 Kathryn L. Evans A1 Michel Didier A1 Siddharthan Chandran A1 Andrew M. McIntosh A1 David J. Price A1 Miles D. Houslay A1 David J. Porteous A1 J. Kirsty Millar YR 2018 UL http://biorxiv.org/content/early/2018/06/17/349365.abstract AB The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-Methyl-D-Aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers.