A valid animal model for the pathogenesis of neurodevelopmental abnormalities of schizophrenia is of potential utility in the prevention and treatment of this illness. Observation of high glycine concentrations in blood and brains of schizophrenics is the basis for developing the animal model proposed in this project. Glycine plays an important role in the physiology of developing and adult brain at the N-methyl-D-aspartate (NMDA) and non-abnormalities of schizophrenia. In this project the validity of a hyperglycinergic rat model will be tested by the following hypotheses: 1. Does lifetime hyperglycinia produce brain (enlarged ventricles) and behavior abnormalities (deficits in PPI) that are characteristic of schizophrenia? 2. Are there particular neurodevelopmental periods in which these effects of glycine are exerted? 3. Can the behavioral abnormalities of the hyperglycinic rats be ameliorated by treatment with typical and atypical antipsychotic drugs? 4. Are there neurochemical abnormalities in the brains of hyperglycinic rats similar to those reported in schizophrenics? The following procedures will test these hypotheses: 1. Experimental rats will be exposed to high glycine concentrations (8 percent of daily chow) from conception to adulthood while controls will receive glucose (8 percent of daily chow). At adulthood, the rats will be assessed for deficits in PPI. These assessments will be repeated after treatment with haloperiodol or clozapine. After sacrifice, brains will be prepared for measuring the size of various structures by computer-assisted planimetry. 2. To find the period of neurodevelopmental vulnerability to hyperglycinia, rats will be exposed to high glycine concentrations in various stages of development during gestation and postnatal life. At adulthood they will undergo the above-described experiments. 3. Littermates of the various groups of rats at adulthood that have undergone the behavioral assessments will be sacrificed for assay of brain biogenic amines and amino acid neurotransmitters from specific brain structures.
