Thalamic Glutamate Dysregulation in Schizophrenia

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DESCRIPTION (provided by applicant): This project is designed to examine the expression of glutamate receptors and related interacting proteins in the thalamus from patients with schizophrenia and a comparison group. Converging lines of evidence indicate that there are region specific alterations in glutamatergic neurotransmission in schizophrenia, particularly in the prefrontal and cingulate cortex, and hippocampus. Recent postmortem and imaging studies have also implicated the thalamus, a region possessing significant glutamatergic efferent and afferent connections between the aforementioned brain regions. Highlighting the potential importance of normal thalamic function are its roles in processing of sensory information and regulation of consciousness, neural processes that may be altered in schizophrenia. The glutamate hypothesis of schizophrenia is supported by pharmacological evidence suggesting involvement of the NMDA receptor, and we have previously demonstrated changes in NMDA receptor stoichiometry in thalamus in this illness. The postsynaptic NMDA receptor complex also includes glutamate receptor interacting proteins that are critical for normal receptor assembly, trafficking, insertion in the plasma membrane, and activation. In addition, colocalization and stimulus specific activation of AMPA receptors are required for initiation of long term potentiation and other NMDA receptor-mediated correlates of neuroplasticity. Thus, we hypothesize that there are abnormalities in the expression of the NMDA and/or AMPA receptors, as well as abnormalities of glutamate receptor interacting proteins associated with the postsynaptic receptor signaling complex in the thalamus in schizophrenia. Accordingly, we will examine the expression of these molecules in postmortem brain samples from schizophrenics and controls. We propose to examine mRNA and protein expression for NMDA and AMPA receptor subunits, as well as proteins that have been identified as interacting partners with these receptors. While evidence has accumulated to support the concept of a disturbance of glutamatergic neurotransmission in schizophrenia, most previous studies have been limited in scope, often focusing on a single molecule and a single level of gene expression. We propose to conduct a detailed examination of functionally linked molecules in the postsynaptic receptor complex, by measuring transcript and protein levels expressed in functionally distinct thalamic nuclei. Further, we will perform cell level studies that will permit comparisons of changes in mRNA expression by intrinsic GABAergic neurons and glutamatergic relay neurons. At the conclusion of this set of experiments, we will have a clearer understanding of the molecular expression of proteins associated with the postsynaptic NMDA receptor complex in the thalamus in schizophrenia. Examination of the expression of these molecules critical for neurotransmission in the thalamic glutamate synapse will highlight abnormalities that can be more profitably targeted for the generation of novel treatment modalities for this disabling illness.