Molecular Mechanism of Prefrontal Glutamate and Dopamine Interpaly and Neuregulin---Mediated Signaling in Animal Model of Schizophrenia (I)

Schizophrenia is a major mental illness characterized by psychosis, delusion, blunted emotions, paranoid ideation, motor abnormalities and cognitive impairment, which results in impaired functioning in work, self-care, independent living and interpersonal relationships Although conventional antipsychotics by blocking dopamine D2-like receptors are widely recognized in treatment of schizophrenia, there is considerable recent evidence linking defects in glutamatergic neurotransmission to the psychiatric manifestation of schizophrenia. It has been proposed that deficit symptoms in schizophrenia are associated with prefrontal glutamine and dopamine (in particular, prefrontal D1 receptor pathway) hypofunction whereas psychotic symptoms are associated with subcortical dopamine hyper-reactivity. Hence, the main aim of this project is first, to understand the molecular mechanism of prefrontal glutamate and dopamine as well as sub-cortical dopamine abnormality in an animal model of schizophrenia, i.e. subchronic phencyclidine (PCP)-treated and as supplement, methamphetamine-treated rats. In addition, a recently identified candidate gene, neuregulin (NRG1) has been associated with pathogenesis of schizophrenia and, it was found neuregulin could regulate the expression of NMDA receptors via acitvation on it receptors, erbB3 and erbB4. Hence, in the second part of the project, we will investigate if there is(are) alteration(s) in neuregulin-erbB signaling in PCP-treated animals and examine the role of NRG1 on PCP-induced behavioral and neurochemical abnormalities. To achieve these goals, we will first establish the animal model of schizophrenia, taking advantage of well-documented PCP-treated rats in producing schizophrenia-like positive (hyperlocomotion and stereotypy) and negative (deficit working memory) behavioral syndromes. The model system will allow us to assess (1) the progressive changes in glutamate- and dopamine-receptor mediated cellular event(s) in the prefrontal cortex as well as in the nucleus accumbens and, if there are accumulations of endogeneous NMDA antagonists, kynurenic acid and NAAG in the prefrontal cortex; (2) the expression of neuregulin and its receptor erbB3 and erbB4 in the prefrontal cortex and, changes in erbB receptor-mediated down-stream signaling (i.e. MAPKs and PI3K/Akt). (3) To understand the details in regulation of neuregulin-erbB on NMDA receptor, and/or possible dopamine D1 receptor, we will examine in primary cerebral cortex neuronal cultures, the effect of neuregulin on binding and expression of particular receptor subtypes, and receptor-mediated cellular signaling. (4) After we gained the basic knowledge from proposed experiments, various pharmacological manipulations will be applied to test if particular drugs (receptor ligand or signal modulator) would adjust the abnormal behaviors or biochemical events that are triggered by chronic PCP treatment. Through proposed 3-year study, we will collaborate intimately with the other projects (electrophysiology, functional neuroanatomy and zebra fish developmental biology) in order to assess the same topic with different research approaches. It is expected through intensive and integrated study, we will be able to delineate the interrelationship between prefrontal glutamate/dopamine and limbic dopamine system in PCP-treated animals. In addition, we are able to identify the significant role of neuregulin-erbB pathway in association with glutamate/dopamine activity in schizophrenia model.

Project ID:PC9408-2175
External Project ID:NSC94-2745-B182-007-URD