Project Summary

Lorna W. Role, Ph.D. (Distinguished Investigator 2007) of the Research Foundation for Mental Hygiene, Inc., plans to perform follow-up in vivo studies about the relationship of the Nrg1 gene to schizophrenia. Prior studies in Dr. Role’s laboratory demonstrated that mice with genetic deficits in Nrgl expression have altered migration, connectivity and plasticity of cortical interneurons. In addition, thanks to NARSAD support in 2000, she embarked on comprehensive studies of Type I11 Nrgl that implicate this isoform per se in the regulation of hippocampal synaptic plasticity and in short- and long-term cognitive function and in sensorimotor gating behaviors. In 2002, Nrgl also was identified as a schizophrenia susceptibility gene. Dr. Role now proposes to move these studies to the next level of analysis by examining the interaction of genetic deficits in Nrgl with those of MAP-6 (STOP) in electrophysiological studies of awake-behaving mice. STOP knock-out mice are viable but they display elevated amphetamine-induced dopamine release in nucleus accumbens, decreased release in cortex and disturbed synaptic plasticity in Schaffer collateral-CAl pyramidal cells. In addition STOP null mice, like Nrgl heterozygous mice have diminished pre-pulse inhibition and maternal nurturing deficits. Particularly striking is that aspects of these phenotypes are reversed by antipsychotic medication. To further test the concept that interactions between multiple genes implicated in distinct and overlapping aspects of schizophrenia-related phenotypes might provide better models of this complex disorder, she proposes to extend the in vitro gene-chimeric approaches she developed previously to in vivo analyses of cortico-limbic circuits and behaviors. The proposed studies represent an entirely new set of approaches for Dr. Role: in vivo electrophysiological recording in awake-behaving mice. The proposed paradigm shift to in vivo analyses will allow her to directly assess disease-relevant issues and to develop quantifiable assays of potential therapeutics that could lead to the development of early intervention pharmacotherapies for neuropsychiatric disorders.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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