DISC1 regulates N-methyl-D-aspartate receptor dynamics: abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness

Abstract

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 the 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.

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte–myelin dysfunction

“…To evaluate whether this in vitro phenotype might be replicated in an in vivo context we next examined a novel mouse model engineered to model the effects of the t(1;11) translocation on DISC1 expression [34]. This mouse mimics the translocationinduced gene fusion that abolishes full-length DISC1 expression from one allele and produces chimeric transcripts encoding deleterious truncated/chimeric forms of DISC1 from the derived chromosome 1 [34,35]. Here, upon co-staining for MBP, a myelin marker, and CASPR, a paranodal marker, in mouse cortices at postnatal day 21 ( Fig.…”

Disrupted‐in‐schizophrenia 1 functional polymorphisms and D2/D3 receptor availability: A [11C]‐(+)‐PHNO imaging study

“…We have recently shown association between the serine allele of Ser704Cys and increased striatal dopamine synthesis capacity in healthy participants . Interestingly, recent studies indicate the t (1;11) translocation may increase the risk of psychosis through various other mechanisms, including altered DNA methylation, regulation of N‐methyl‐D‐aspartate receptors (NMDAR) motility and/oradded effects of the translocation and a variable subset of potential phenotypic polymorphisms . Future studies should aim at clarifying how the DISC1 protein interacts with the D 2 R and whether the DISC1 Ser704Cys, Leu607Phe and Arg264Gln polymorphisms affect D 2 R availability in clinical populations.…”

Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness

“…Carriers of the t(1;11) translocation also have decreased glutamate levels in the dorsolateral prefrontal cortex 9 . Moreover, transcriptome analysis of induced pluripotent stem cell (IPSC)-derived cortical neurons from t(1;11) translocation carriers 12 found enrichment for dysregulated genes at putative schizophrenia and depression loci discovered through large-scale GWAS and CNV studies 1 – 3 , potentially identifying some of the genes of interest at those loci, and indicating that the t(1;11) translocation may trigger disease pathways shared with schizophrenic patients who are not translocation carriers.…”

“…To examine the impact of DISC1 disruption in isolation from the additional complexities of DISC2 disruption and loss of normal DISC1FP1 function, and of potential genetic modifiers, we have utilised a mutant mouse that accurately recapitulates the effects of the translocation upon DISC1 expression 12 . IPSC-derived neural precursor cells and cortical neurons from t(1;11) translocation carriers exhibit reduced DISC1 expression 12 .…”

“…To examine the impact of DISC1 disruption in isolation from the additional complexities of DISC2 disruption and loss of normal DISC1FP1 function, and of potential genetic modifiers, we have utilised a mutant mouse that accurately recapitulates the effects of the translocation upon DISC1 expression 12 . IPSC-derived neural precursor cells and cortical neurons from t(1;11) translocation carriers exhibit reduced DISC1 expression 12 . Chimeric transcripts encoding aberrant C-terminally truncated chimeric forms of DISC1 are also produced in the IPSC-derived neural cells as a result of the fusion between the DISC1 and DISC1FP1 genes on the derived chromosome 1 12 , 29 .…”