PT  - JOURNAL ARTICLE
AU  - Elise L.V. Malavasi
AU  - Kyriakos D. Economides
AU  - Ellen Grünewald
AU  - Paraskevi Makedonopoulou
AU  - Philippe Gautier
AU  - Shaun Mackie
AU  - Laura C. Murphy
AU  - Hannah Murdoch
AU  - Darragh Crummie
AU  - Fumiaki Ogawa
AU  - Daniel L. McCartney
AU  - Shane T. O’Sullivan
AU  - Karen Burr
AU  - Helen S. Torrance
AU  - Jonathan Phillips
AU  - Marion Bonneau
AU  - Susan M. Anderson
AU  - Paul Perry
AU  - Matthew Pearson
AU  - Costas Constantinides
AU  - Hazel Davidson-Smith
AU  - Mostafa Kabiri
AU  - Barbara Duff
AU  - Mandy Johnstone
AU  - H. Greg Polites
AU  - Stephen Lawrie
AU  - Douglas Blackwood
AU  - Colin A. Semple
AU  - Kathryn L. Evans
AU  - Michel Didier
AU  - Siddharthan Chandran
AU  - Andrew M. McIntosh
AU  - David J. Price
AU  - Miles D. Houslay
AU  - David J. Porteous
AU  - J. Kirsty Millar
TI  - DISC1 regulates N-Methyl-D-Aspartate receptor dynamics: Abnormalities induced by a <em>Disc1</em> mutation modelling a translocation linked to major mental illness
AID  - 10.1101/349365
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 349365
4099  - http://biorxiv.org/content/early/2018/06/17/349365.short
4100  - http://biorxiv.org/content/early/2018/06/17/349365.full
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.