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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.

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.

SUBMITTER: Bonneau M

PROVIDER: S-EPMC7895946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recent studies have investigated the effectiveness of aerobic exercise to improve physical and mental health outcomes in schizophrenia; however, few have explicitly explored the impact of aerobic exercise on neural microstructure, which is hypothesized to mediate the behavioral changes observed. Neural microstructure is influenced by numerous genetic factors including DISC1, which is a major molecular scaffold protein that interacts with partners like GSK3β, NDEL1, and PDE4. DISC1 has been shown to play a role in neurogenesis, neuronal migration, neuronal maturation, and synaptic signaling. As with other genetic variants that present an increased risk for disease, mutations of the DISC1 gene have been implicated in the molecular intersection of schizophrenia and numerous other major psychiatric illnesses. This study investigated whether short-term exercise recovers deficits in neural microstructure in a novel genetic Disc1 svΔ2 rat model. Disc1 svΔ2 animals and age- and sex-matched controls were subjected to a treadmill exercise protocol. Subsequent ex-vivo diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) compared neural microstructure in regions of interest (ROI) between sedentary and exercise wild-type animals and between sedentary and exercise Disc1 svΔ2 animals. Short-term exercise uncovered no significant differences in neural microstructure between sedentary and exercise control animals but did lead to significant differences between sedentary and exercise Disc1 svΔ2 animals in neocortex, basal ganglia, corpus callosum, and external capsule, suggesting a positive benefit derived from a short-term exercise regimen. Our findings suggest that Disc1 svΔ2 animals are more sensitive to the effects of short-term exercise and highlight the ameliorating potential of positive treatment interventions such as exercise on neural microstructure in genetic backgrounds of psychiatric disease susceptibility.

Project description:BackgroundThis study examined outcomes for two groups of stroke survivors treated in Veteran Health Administration (VHA) hospitals, those with a severe mental illness (SMI) and those without prior psychiatric diagnoses, to examine risk of non-psychiatric medical hospitalizations over five years after initial stroke.MethodsThis retrospective cohort study included 523 veterans who survived an initial stroke hospitalization in a VHA medical center during fiscal year 2003. The survivors were followed using administrative data documenting inpatient stroke treatment, patient demographics, disease comorbidities, and VHA hospital admissions. Multivariate Poisson regression was used to examine the relationship between patients with and without SMI diagnosis preceding the stroke and their experience with non-psychiatric medical hospitalizations after the stroke.ResultsThe study included 100 patients with SMI and 423 without SMI. Unadjusted means for pre-stroke non-psychiatric hospitalizations were higher (p = 0.0004) among SMI patients (1.47 ± 0.51) compared to those without SMI (1.00 ± 1.33), a difference which persisted through the first year post-stroke (SMI: 2.33 ± 2.46; No SMI: 1.74 ± 1.86; p = 0.0004). Number of non-psychiatric hospitalizations were not significantly different between the two groups after adjustment for patient sociodemographic, comorbidity, length of stay and inpatient stroke treatment characteristics. Antithrombotic medications significantly lowered risk (OR = 0.61; 95% CI: 0.49-0.73) for stroke-related readmission within 30 days of discharge.ConclusionsNo significant differences in medical hospitalizations were present after adjusting for comorbid and sociodemographic characteristics between SMI and non-SMI stroke patients in the five-year follow-up. However, unadjusted results continue to draw attention to disparities, with SMI patients experiencing more non-psychiatric hospitalizations both prior to and up to one year after their initial stroke. Additionally, stroke survivors discharged on antithrombotic medications were at lower risk of re-admission within 30 days suggesting the VHA should continue to focus on effective stroke management irrespective of SMI.

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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.

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