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

  • ️Fri Jan 01 2021

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

Marion Bonneau et al. Transl Psychiatry. 2021.

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.

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Conflict of interest statement

The authors declare that they have no conflict of interests. A.M.M. has received research support from Eli Lilly and Company, Janssen and the Sackler Trust and speaker fees from Illumina and Janssen. A.C.V. has received research support from F. Hoffman La Roche and UCB Biopharma SPRL. M.L. is a full-time employee of Sylics (Synaptologics B.V.), a private company that offers mouse phenotyping services. A.B.S. is a shareholder of Alea Biotech B.V., a holding of Sylics (Synaptologics B.V.). M.D. is based at Sanofi.

Figures

Fig. 1
Fig. 1. The Der1 mutation targets specific cell types in heterozygous cortex and hippocampus.

a Disc1 RNASeq reads normalised to total reads per sample in wild-type versus heterozygous Der1 cortex and hippocampus. b Heat maps of the top 500 dysregulated genes identified by RNASeq of wild-type versus heterozygous Der1 cortex and hippocampus. c, d EWCE analysis of heterozygous Der1 cortex and hippocampus, respectively, in mouse brain cell classes. Asterisk, significance after Bonferroni correction; Emb embryonic, Hyp hypothalamic, SD standard deviation. e Parvalbumin expression in hippocampal sections from 9-week-old mouse brain. Enlarged regions showing parvalbumin-expressing interneurons are indicated by boxes. Scale bars, 100 μm. f Average density of parvalbumin-expressing interneurons. Hippocampus refers to the whole hippocampal formation. Data were analysed by Kruskal–Wallis one-way ANOVA, p = 0.07 for the dentate gyrus, p = 0.049 for the hippocampal formation. The horizontal line on graphs for each sample, an average of values; WT wild type, HET heterozygous Der1, HOM homozygous Der1, DG dentate gyrus, *p < 0.05.

Fig. 2
Fig. 2. Consequences of the Der1 mutation.

a Top relevant canonical pathway predictions for heterozygous Der1 cortex using whole gene, DESeq2 or whole gene and exon-level, DESeq2 + DEXSeq data. Asterisks indicate pathways highlighted in both cases. Where IPA predicts a direction of change, this is indicated by a z score, with positive z scores indicating upregulation. b Altered gene expression in the ‘CREB signalling in neurons’ canonical pathway in heterozygous Der1 cortex, determined using the whole gene and exon-level DESeq2+DEXSeq data. To provide additional information, genes encoding calcium channels (CaCh), metabotropic glutamate receptors (mGLUR), ionotropic glutamate receptor subunits (iGLUR) and structural synaptic components have been added to the pathway using the IPA ‘Build’ tool. Transcripts encoding components from the whole pathway are dysregulated at the whole gene and/or isoform level, including ionotropic AMPA and NMDA glutamate receptor subunits, metabotropic glutamate receptors and voltage-gated calcium channels, all of which can control the calcium ion influx or G-protein activation that initiates the pathway. Genes encoding several synaptic scaffolds that are required to generate and maintain synapse structure/size and/or anchor glutamate receptors and calcium channels are also dysregulated, including Shank1, Homer1 and Dlg1/3/4, neurexins and neuroligins. Also dysregulated are genes encoding various factors downstream of glutamate receptors and calcium channels that activate the cAMP-dependent transcription factor CREB, such as various forms of Camk2 and adenylyl cyclases. The transcriptional machinery is additionally affected, including the cAMP-dependent transcription factor complex. Double outlines indicate protein complexes and classes, the components of which can be found in Supplementary Table 2a, b. Colour intensity represents the strength of gene expression change, with graded colour within double-outlined symbols representing the overall direction of change within protein complexes. Green, downregulated; red, upregulated; *genes identified by DEXSeq; ** genes identified by DEXSeq and DESeq2. c Sunburst plots showing SynGO- annotated synaptic functions of the dysregulated proteins found in homozygous Der1 hippocampus synaptosomes (FDR-adjusted p value < 0.05). Note that synaptosomes are enriched for the complete presynaptic terminal, the postsynaptic membrane and the postsynaptic density, as well as membranes originating from organelles such as the Golgi and endoplasmic reticulum. d Quantification of AMPA and NMDA receptor currents by whole-cell patch clamping of neurons cultured from Der1 hippocampus. Data were analysed by one-way ANOVA, p = 0.03. The horizontal line on graphs for each sample, an average of values; WT wild type, HET heterozygous Der1, HOM homozygous Der1, *p < 0.05.

Fig. 3
Fig. 3. The Der1 mutation dysregulates canonical pathways and genes related to schizophrenia and depression in heterozygous Der1 cortex.

a Canonical pathway predictions for putative schizophrenia risk genes, and for orthologues of putative schizophrenia and depression risk genes that are dysregulated at the whole-gene and exon-level, as identified using DESeq2 + DEXSeq data. b, c Altered schizophrenia risk gene orthologue expression in the ‘Synaptic long-term depression’ and ‘CREB signalling in neurons’ canonical pathways, respectively. Double outlines indicate protein complexes and classes, the components of which can be found in Supplementary Table 2a, b. To provide additional information, genes encoding ionotropic glutamate receptor δ subunits (Grid), AMPA receptor subunits (AMPAR), voltage-gated calcium channel subunits (VGCC), calcium channels (CaCh), ionotropic glutamate receptor subunits (iGLUR) and structural synaptic components have been added to the pathways using the IPA ‘Build’ tool. *Genes identified by DEXSeq; red, dysregulated putative schizophrenia risk gene orthologue.

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