Schizophrenia is a debilitating neurodevelopmental illness that honors no racial or ethnic boundaries. Initial research into its etiology has focused on hyperdopaminergic activity based on clinical observations that dopamine blocking drugs diminish positive psychotic symptoms. Recent findings have implicated the role of glutamate receptors in schizophrenia. These studies propose that reduced NMDA receptor function stimulates abnormally high glutamate release within the synapse, which subsequently leads to unregulated excitation, disinhibition of inhibitory pathways, and neuronal degeneration. Such impaired glutamatergic neurotransmission is potentially associated with the abnormal cognitive, behavioral and memory functions characteristic of schizophrenia. The NMDA receptor hypofunction theory of schizophrenia guides two hypotheses proposed in this research: (1) Glutamate receptor dysfunction in schizophrenia is dependent on alterations in NMDA and AMPA receptor subunit composition in specific brain regions; and (2) Atypical neuroleptics reduce schizophrenic symptoms through cellular mechanisms that either restore NMDA function or circumvent NMDA dysfunction. The primary objective of our research is to contribute to a fundamental understanding of schizophrenia and it's underlying physiological mechanisms. We will contribute to this knowledge base by examining three aims that test these hypotheses.
AIM 1 : To localize NMDA and AMPA glutamate receptor subunits by immunocytochemistry and light microscopy in normal rat brains and PCP-psychosis induced rat brains.
AIM 2 : To elucidate the effects of atypical neuroleptics on relative NMDA and AMPA receptor subunit composition in normal rat, PCP-psychosis induced rat, normal neuroleptic treated rat and neuroleptic treated, PCP-psychosis induced rat brains.
AIM 3 : To examine potential physiological mechanisms of action that may underlie the effects of atypical neuroleptics on NMDA and AMPA-mediated glutamatergic neurotransmission in normal, normal neuroleptic treated, PCP-psychosis induced and PCP-psychosis induced neuroleptic treated rat brains. While the overall scientific goal of this K08 application is to elucidate the role of glutamate receptors in schizophrenia's pathophysiology, the long-term intent of this proposal is to establish my career as a clinical scientist with the potential to develop as an independent researcher.
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| Mokin, Maxim; Lindahl, Josette S; Keifer, Joyce (2006) Immediate-early gene-encoded protein Arc is associated with synaptic delivery of GluR4-containing AMPA receptors during in vitro classical conditioning. J Neurophysiol 95:215-24 |
| Lindahl, Josette S; Keifer, Joyce (2004) Glutamate receptor subunits are altered in forebrain and cerebellum in rats chronically exposed to the NMDA receptor antagonist phencyclidine. Neuropsychopharmacology 29:2065-73 |
