Project Summary

Eric R. Kandel, M.D. (Distinguished Investigator 2005) of Columbia University, notes that psychiatry has so far identified very few genes involved in major mental illnesses. One of these is the neuregulin gene. Moreover, little is known about the neural circuits affected by most major psychiatric disorders. As a result, until recently, no satisfactory animal models for these disorders existed. To address this deficiency, Dr. Kandel has begun to develop mouse models of schizophrenia. Since the entire spectrum of schizophrenia symptoms cannot be modeled in a mouse, he has focused on cognitive deficits in working memory, which appear to reflect a core genetic vulnerability in this illness. He has addressed the molecular underpinnings of the cognitive symptoms of schizophrenia, in particular the molecular changes in the prefrontal cortex responsible for the defect in working memory. Two major hypotheses in schizophrenia research, will be addressed: the dopamine (DA) hypothesis states that an imbalance in the DA system is responsible for many of the symptoms of schizophrenia. Currently, the predominant view is that hyperactiyity in the mesolimbic/nigrostriatal DA system may lead to positive symptoms whereas hypoactivity in the mesocortical system may lead to cognitive defects. The GLU hypothesis states that the primary deficit is glutamatergic leading to secondary changes in the DA system. Dr. Kandel will generate 3 mouse models, each of which tests a specific DA or GLU dysfunction observed in schizophrenic patients. These experiments demonstrate that mouse models can serve as valuable models of psychiatric disease. Following his success with these models which test specific pathophysiological ideas about schizophrenia, he proposes to extend this research on mouse models of schizophrenia by testing candidate genes that now have been identified in patient population studies. These include: 1) COMT (Catecholamine-o-methyl transferase), 2) the nicotinic α7 receptors, and 3) Neuregulin-1. Initially, he will focus on Neuregulin-1, as a risk haplotype of this gene has been identified in two independent schizophrenic populations, Scottish and Icelandic; a reduction of 42% in the expression of erbB3, one of the neuregulin-1 receptors, has been found to occur in the prefrontal cortex of schizophrenic patients; and mice lacking one copy of the neuregulin-1 gene in the whole brain have a defect in pre-pulse inhibition, a cognitive function which is also observed in schizophrenia. Neuregulin is also critical for brain development and may have a role in synaptic plasticity. In particular, neuregulin can regulate the NMDA receptor and thereby modify glutamatergic transmission. He will first examine these mice cognitively, physiologically, and neuroanatomically to characterize any candidate schizophrenia-like defect. He will then explore the possible action of developmental mechanisms by seeing to what degree any observed defect persists when the gene is turned off. If there is persistence, he will explore the critical period of expression. He proposes to further advance the development of mouse models of schizophrenia by combining genetic mouse models to analyze the polygenic nature of the cognitive symptoms of schizophrenia. Once he has analyzed the phenotype of the NRG mutant mice, he will cross them to one or more of our other models he already has on hand to create a multigenic defect in the mouse. In each case, he will attempt to determine in these multigenic models whether there is a synergistic effect as determined either by enhancement of the defect in working memory or the emergence of other defects that might be more associated with the positive symptoms. This would be a first attempt to examine the interaction between candidate genes in an animal model of a complex polygenic psychiatric disorder.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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