Project Summary

David D. Mott, Ph.D. (Young Investigator 2004) of Emory University, proposes to study the mechanism for neural injury that might be occurring in schizophrenia via the NMDA receptor for glutamate, the most important excitatory transmitter in the brain. Studies show that NMDA receptor antagonists in humans create schizophrenia-like symptoms, suggesting reduced NMDA receptor activity contributes to the disorder. These antagonists produce neurodegenerative changes in the posterior cingulate and retrospenial, or PC/RS parts, of the corticolimbic regions of rat brains. The antagonists lead to hyperexcitation of cholinergic and glutaminergic inputs to the PC/RS cortex, a process dependent upon activation of both muscarinic acetylcholine receptors (mAchRs) and AMPA/kainate receptors, as antagonists of either receptor block the neurotoxicity. Dr. Mott hypothesizes that during NMDA receptor antagonism, kainate receptors are activated by the hyperactive glutaminergic input to PC/RS cortex. The hyperexcitable cholinergic input then activates mAchR, potentiating the kainate response and causing neuronal injury. In this project, he will test this hypothesis using both in vitro and in vivo methods. The results should improve understanding of the role of kainate receptors in schizophrenia and potentially identify novel targets for new antipsychotic drugs.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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