Identifying molecular path of behavioural phenotype in schizophrenia

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DESCRIPTION (provided by applicant): Several behavioral/neurophysiological abnormalities are proposed as alternatives to the clinical phenotype in marking the liability for schizophrenia. These intermediate phenotypes may mark sub-components of disease risk and more specific biochemical paths contributing to the etiology of schizophrenia. One highly reproducible phenotype is the smooth pursuit eye movement (SPEM, also called eyetracking) abnormality, replicated by over 50 studies with few negative results. Evolutionally this phenotype is unique in that SPEM is a behavior only present in primates. Unfortunately until now there is a void of knowledge in our understanding of the molecular basis of abnormal eyetracking, largely due to the evolutionary characteristics of this phenotype, which limits the development of small animal models. The challenge is how this unique phenotype can be translated into tangible biochemical studies, which is a necessary step to describe the path from genes to behavioral deficits and thereby to establish new molecular treatment targets. We have developed a strategy that allows us to probe the molecular mechanisms of SPEM deficits in schizophrenia. Recent studies suggest that predictive pursuit deficit (PPD) may underlie the eyetracking abnormality in schizophrenia. Predictive pursuit is the primary mechanism for maintaining smooth pursuit in primates. Imaging studies have identified several candidate anatomic loci of the SPEM deficit in schizophrenia. Among these loci, the consistently replicated finding is reduced activation in the frontal eye fields (FEF) during SPEM. This region will be the focus of the proposed study. Predictive pursuit deficit is present in schizophrenia patients and some 1st degree relatives. Critically, family studies examining this refined phenotype revealed a high familiality. The high familiality permits a reasonable chance to identify postmortem tissues more homogenously associated with PPD using proxy measurement in living family members. Combining knowledge learned from functional imaging and family studies, we plan to select subphenotype-specific postmortem brain tissue for the purpose of screening transcripts associated with PPD in schizophrenia. Schizophrenia is a devastating brain illness affecting 1% of our population. There is lack of effective treatment for core physiological and cognitive deficits associated with this illness. This project aims to identify genes and gene products associated with one of these core deficits called eyetracking abnormality in schizophrenia so that drugs can be developed to treat these core physiological and cognitive deficits.