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

Abstract

A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.

Mutations in DISC1 alter IP3R and voltage-gated Ca2+ channel functioning, implications for major mental illness

“…At least 50 different transcripts of DISC1 are expressed dynamically over time in various brain regions [ 44 , 65 , 66 ]. Different cell types in adult cortical brain regions express unique profiles of DISC1 transcripts, which in turn yield, or are predicted to yield, unique DISC1 interactomes for a given cell type over a lifetime with greatest interest in hippocampal and cortical glutamatergic pyramidal neurons and GABA inhibitory interneurons [ 53 , 62 , 65 , 67 , 68 ].…”

“…Nevertheless, these interactions have functional significance since Itpr1 mRNA and DISC1 colocalize in hippocampal dendrites where release of Ca 2+ from IP 3 Rs is critical for initiating long-term changes in synaptic plasticity [ 108–113 ]. Disc1 knockout mice show normal brain cytoarchitecture [ 68 ] but exhibit abnormal synaptic activity, impaired maintenance of LTP, and altered emotional behaviors [ 114 ]; all functions that involve synaptic plasticity and cognitive behaviors often disrupted in Schz. This phenotype was also observed in hippocampal slices exposed to a cell permeable peptide, which blocks DISC1 binding to Itpr1 mRNA [ 106 ], thus linking DISC1 to Ca 2+ -mediated synaptic plasticity.…”

“…Moreover, a recent, in depth RNAseq analysis of the Der1 mouse model, which expresses reduced levels of Disc1, revealed prominent dysregulation of several Ca V α 1 subunits and Ca V β2. Subsequent proteomics and pathway analysis identified Ca 2+ signaling as at risk in Der1 and overlapping with genetic risk factors found in Schz GWAS [ 68 ].…”