Schizophrenia is a chronic debilitating mental disorder characterized by positive symptoms (psychosis), negative symptoms (apathy) and subtle cognitive impairments as well as physiologic abnormalities such as hypofrontality, disrupted eye tracking and altered evoked cortical potentials. The syndromic features can best be replicated in normal volunteers by administration of subanaesthetjc doses of dissociative anaesthetics, which are non-competitive antagonists at the NMDA receptor. More recent postmortem, metabolic and genetic studies have provided circumstantial evidence that hypofunction of a discrete population of NMDA receptors can contribute to the symptoms of schizophrenia, at least in some patients. Furthermore, placebo controlled clinical trials have shown that agents that act at or potentiate the glycine modulatory site (GMS) on the NMDA receptor-D-cycloserine, glycine, D-serine and sarcosine-all reduce negative symptoms, generally improve cognition and in the cases of D-serine and sarcosine also reduce positive symptoms in schizophrenic subjects receiving typical antipsychotic medications. During the previous 9 years of support, the goal of this research grant has been to understand the modulation of glutamatergic neurotransmission, specifically the disposition of N-acetyl-aspartyl-glutamate (NAAG) as it may relate to the pathophysiology of schizophrenia. Given the evidence that GMS function may be impaired in schizophrenia and that GMS agonists reduce symptoms in the disorder, we now propose using recombinant DNA strategies to characterize the regulation of GMS function. The availability of glycine at the synaptic NMDA receptors is determined by the activity of the glycine transporter, GlyT1 and that of D-serine by the activity of serine racemase, its synthetic enzyme, and D-amino acid oxidase, its degradative enzyme; however, the precise mechanisms determining their synaptic concentrations as weIl as the interaction between these 2 ligands are poorly understood. Therefore, we propose manipulating the expression of GlyT-1 and serine racemase by transgenic and null mutation strategies and examining the consequences on brain synaptic chemistry, hippocampal electrophysiology and behavior. We hypothesize that conditions that produce low GMS occupancy may create behavioral homologues of components of the schizophrenia syndrome such as cognitive and social impairments whereas high occupancy may be associated with enhanced cognitive performance. Findings from these studies should shed light on the pathophysiology of schizophrenia and may identify potential strategies for novel treatments.
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