Project Summary

Zhen Yan, Ph.D. (Independent Investigator 2004) of State University of New York, Buffalo, will explore the role of both dopamine and glutamate systems in schizophrenia using a rat model. Drugs used to treat schizophrenia have focused on the dopamine family of receptors, but a model of schizophrenia suggests involvement of both neurotransmitter systems, dopamine and glutamate. Effective schizophrenia drugs inhibit either the D2 family of receptors (typical) or D4 receptors (atypical). Administration of phencyclidine (PCP), an NMDA receptor antagonist, produces behavioral symptoms very similar to schizophrenia in humans and animals. These studies indicate dysfunction of the dopaminergic and glutamatergic systems play important roles in the abnormal changes related to schizophrenia. Dr. Yan will seek to understand how D4 signaling is involved in the regulation of synaptic transmission in the prefrontal cortex (PFC), which is critical for high-level “executive” processes and how this regulation is altered in schizophrenia. She hypothesizes that the NMDA receptor channel is potentially a key cellular substrate for D4 signaling in PFC and disruption of its regulation by D4 receptors in schizophrenia might contribute to the cognitive and behavioral impairment. Combined electrophysiological, pharmacological, biochemical and molecular analyses will be used to test these hypotheses. She will investigate a novel mechanism for D4 receptors to modulate PFC neuronal activity, which potentially plays a significant role in the regulation of cognition and emotion. This may shed light on how the two prominent models of schizophrenia, hyperdopaminergia and hypoglutamatergia, may be mechanistically linked and would provide important insights into the cellular and molecular basis of schizophrenia, and possibly new drug treatments.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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