The career development and research program described in this proposal supports the application for a Mentored Research Scientist Development Award for Dr. Kenneth N. Fish, and is intended to provide the candidate with the background knowledge, research experience, and research management skills that will prepare him for an independent research career in schizophrenia. Training will take place at the Harold L. Dorris Neurological Research Center in the Department of Neuropharmacology (Dr. Floyd E. Bloom, Chair) of the Scripps Research Institute, under the direct supervision of Dr. Tamas Bartfai. Dr. Bartfai is highly qualified to serve as Preceptor for the Candidate, because of his experience with the methodologies to be used, his active research program in depression and schizophrenia, and his commitment to the development of junior research scientists. The Department of Neuropharmacology emphasizes a multi-disciplinary approach to problems of mental disorders. Thus, this is an ideal environment for the Candidate to materialize his goal of developing a multidisciplinary research approach to the neurobiology of schizophrenia. The overall objective of the research plan is to perform a thorough analysis of the reeler and scrambler mice to define test parameters that will be used to study new mouse models and to determine their applicability as models to study schizophrenia. Tests will include a morphological analysis of the neocortex, cerebellum, and hippocampus using three-dimensional reconstruction with NeuroZoom, immunocytochemical analysis of DA, GLU, and GABA expression, quantitative behavioral measurements [prepulse inhibition (PPI) of the startle response], and their responsiveness to clinically effective antipsychotics (haloperidol, risperidone, and clozapine). In addition, to further characterize the reeler phenotype we will generate a transgenic mouse in which reelin expression is temporally regulated and generate a mouse model that has a conditional block of reelin function to induce specific changes in brain morphology that are required to alter prepulse inhibition and/or induce ataxia. These studies will advance our understanding of how neurodevelopmental abnormalities relate to behavioral changes and will assist in the development of new antipsychotic drugs with relevance to schizophrenia.
