The overarching aim of thisgrant is to examine the role of glutamatergic neurotransmission,in particular that ofjgiutamatergic efferents rom the prefrontal cortex (RFC), in the functional abnormalities that may be ?elated to schizophrenia.One of our key findings during the past funding period has been that NMDA receptor hypofunction in b having animals increases the firing of RFC pyramidal cells consistent with the idea that cortical GABAint irneurons have a high level of NMDA tonic activation that drives the pyramidal neurons. Based on this progress, it is hypothesized that NMDA receptor hypofunction reduces the inhibitory influence of GABA interneurons on cortical pyramidal cells producing a tonic state of disinhibition at these neurons. We predict that tr is reduced inhibitory control (1) diminishes the capacity of RFC neurons to fire appropriately to task relevant stimuli, and (2) exaggeratesthe phasic impact of glutamate afferentson some pyramidal neurons leading to abnormal activity of RFC projections to dopamine cells resulting in excess dopamine release.The first prediction assumes a constant state of aberration, consistentwithsustained cognitive deficits in schizof: hrenia. The second prediction assumes interrupted changes in dopamine release th^t occur in response to p lasic activationof afferents from regions such as the thalamus and habenula consistent with episodic incidents of psychosis in schizophrenia. We further hypothesize that events at the excitatory afferent-GABAsynapse in the RFC are key for discovering drug targetsthat normalize the impact of jthe reduced inhibitory central on RFC efferents and, hence, may be useful for treatment of schizophrenia. We propose to test these hypotheses using ensemble recording and mierodialysis in behaving rodents. Public health relevance schizophrenia is a major public health concern. This project seeks to develop anew understanding of the pathophysiology of schizophrenia and evaluate novel treatment options for treatment of this disorder.
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