The transgenic ckr mice expressing an insertional mutation develop a progressive behavioral phenotype with motor symptoms resembling those seen in schizophrenia. As schizophrenia is a progressive brain disease of early development that affects forebrain neurons and circuits and ultimately behavior, there may be a relationship between disrupted forebrain development and basal ganglia dysfunction produced by the above insertional mutation. Here we will test this possibility by characterizing the behavioral deficits in ckr mice using a battery of behavioral tests selected to measure aspects of locomotion, hyperactivity, circling and sensorimotor gating. Further, we will test the ability of atypical antipsychotic agents and glutamate receptor agonists at preventing or attenuating the motor dysfunctions in ckr mice. As it is likely that the basic cellular and molecular mechanisms for initial regional and circuit differentiation in the forebrain is similar in most mammals, we propose to examine aberrations in forebrain development in the ckr mouse. This hypothesis is supported by preliminary studies that show enlargement of the lateral ventricles and a paucity of myelin fibers in the transgenic mouse striatum. To accomplish these research aims, the use of various combinations of immuno- and in situ hybridization and histochemical experiments, magnetic resonance neuroimaging techniques, and discrete pharmacological and behavioral manipulations will be used to elucidate further the cause and course related to the pathophysiology of schizophrenia.
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