Project Summary

Venkatesh N. Murthy, Ph.D., (Independent Investigator 2006) of Harvard University, notes that schizophrenia has a significant genetic component and may involve developmental disturbances in the brain. The complex multigenic nature of schizophrenia suggests that single gene disruptions may lead to compensatory adjustments in the brain, but multiple gene disruptions lead to failure of such compensations. Such a hypothesis would predict that disruption of a single candidate gene in model organisms would leave traces of compensation in the brain circuitry that could be revealed by detailed cellular analysis. Dr. Murthy will investigate changes in synaptic function in two different mouse models of schizophrenia--mice lacking the candidate gene disrupted-in-schizophrenia-1 (DISC1), and those lacking the candidate gene dysbindin. He will focus on the hippocampus, since there is evidence for a role of these two genes in hippocampal function in humans. He will first use electrophysiology and optical microscopy to measure functional properties of glutamatergic and GABAergic synaptic inputs to principal neurons during development and in more mature neurons, then will test whether the ability of hippocampal neurons to undergo homeostatic synaptic compensation is altered in neurons lacking DISC1 or dysbindin. Ordinarily, neurons grown in primary cultures respond to persistent changes in neural activity by altering the strength of synapses in a direction that will counter the experimental perturbation. Dr. Murthy will determine whether neurons from DISC1 and dysbindin mutant mice retain this ability to undergo such compensatory changes. This study will provide important information regarding two possible genes for schizophrenia, and also establish valuable physiological assays for future examination of other candidate genes.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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