This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Schizophrenia is a debilitating disorder that's many symptoms include psychosis as well as impairments in sensory motor gating and learning and memory. Findings from studies of the brains of schizophrenic patients have indicated subtle changes in the signaling of the neurotransmitter glutamate as well as reductions in a specific sub-set of inhibitory neurons. These neurons are in part responsible for coordinating the activity of large populations of other neurons. The combination of the above data has been used to propose a hypo-glutamatergic (reduction in glutamate signaling) theory as a potential cause of schizophrenia. This model proposes that a reduction in the excitatory drive (by glutamate) on a specific group of inhibitory neurons prevents them from regulating other circuits in the brain, which gives rise to the symptoms of schizophrenia. Additional data from human populations and animal model systems have established that drugs that block the NMDA glutamate receptor produces behavioral changes consistent with what is seen in schizophrenia populations. While the manipulation of NMDA function has reliably been used to model schizophrenia (in our hands and others), there is virtually no data on alterations in the down stream binding sites from these inhibitory neurons which are proposed to be dysregulated. The goal of the proposed experiments is to carefully examine if direct alterations of inhibitory signaling produce similar deficits and/or are capable of modifying the behavioral and cellular alterations produced by chronic NMDA receptor blockade in an animal model of schizophrenia. Preliminary data collected suggest novel alterations in behavior consistent with schizophrenia. In these experiments we will examine behavior relevant to schizophrenia as well as tissue for alterations observed in patient populations. The detection of any change in either the behavioral deficits or cellular changes associated with NMDA receptor blockade or inhibitory tone in an in-vivo model would contribute a great deal to our understanding of mechanisms involved in schizophrenia. The data may also point toward a novel therapeutic approach to the treatment of schizophrenia.
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