Disc1 point mutations in mice affect development of the cerebral cortex.
ABSTRACT Disrupted-in-Schizophrenia 1 (DISC1) is a strong candidate gene for schizophrenia and other mental disorders. DISC1 regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, and neurotransmitter signaling. Abnormal neuronal morphology and cortical architecture are seen in human postmortem brain from patients with schizophrenia. However, the etiology and development of these histological abnormalities remain unclear. We analyzed the histology of two Disc1 mutant mice with point mutations (Q31L and L100P) and found a relative reduction in neuron number, decreased neurogenesis, and altered neuron distribution compared to wild-type littermates. Frontal cortical neurons have shorter dendrites and decreased surface area and spine density. Overall, the histology of Disc1 mutant mouse cortex is reminiscent of the findings in schizophrenia. These results provide further evidence that Disc1 participates in cortical development, including neurogenesis and neuron migration.
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ABSTRACT: Disrupted-In-Schizophrenia-1 (DISC1) has captured much attention because it predisposes individuals to a wide range of mental illnesses. Notably, a number of genes encoding proteins interacting with DISC1 are also considered to be relevant risk factors of mental disorders. We reasoned that the understanding of DISC1-associated mental disorders in the context of network principles will help to address fundamental properties of DISC1 as a disease gene. Systematic integration of behavioural phenotypes of genetic mouse lines carrying perturbation in DISC1 interacting proteins would contribute to a better resolution of neurobiological mechanisms of mental disorders associated with the impaired DISC1 interactome and lead to a development of network medicine. This review also makes specific recommendations of how to assess DISC1 associated mental disorders in mouse models and discuss future directions.Neuroscience & Biobehavioral Reviews 01/2014; · 10.28 Impact Factor
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ABSTRACT: Drug discovery in psychiatry has been limited to chemical modifications of compounds originally discovered serendipitously. Therefore, more mechanism-oriented strategies of drug discovery for mental disorders are awaited. Schizophrenia is a devastating mental disorder with synaptic disconnectivity involved in its pathophysiology. Reduction in the dendritic spine density is a major alteration that has been reproducibly reported in the cerebral cortex of patients with schizophrenia. Disrupted-in-Schizophrenia-1 (DISC1), a factor that influences endophenotypes underlying schizophrenia and several other neuropsychiatric disorders, has a regulatory role in the postsynaptic density in association with the NMDA-type glutamate receptor, Kalirin-7, and Rac1. Prolonged knockdown of DISC1 leads to synaptic deterioration, reminiscent of the synaptic pathology of schizophrenia. Thus, we tested the effects of novel inhibitors to p21-activated kinases (PAKs), major targets of Rac1, on synaptic deterioration elicited by knockdown expression of DISC1. These compounds not only significantly ameliorated the synaptic deterioration triggered by DISC1 knockdown but also partially reversed the size of deteriorated synapses in culture. One of these PAK inhibitors prevented progressive synaptic deterioration in adolescence as shown by in vivo two-photon imaging and ameliorated a behavioral deficit in prepulse inhibition in adulthood in a DISC1 knockdown mouse model. The efficacy of PAK inhibitors may have implications in drug discovery for schizophrenia and related neuropsychiatric disorders in general.Proceedings of the National Academy of Sciences 04/2014; · 9.81 Impact Factor
- Future Neurology 01/2011; 6:661-677.