A Genetic and PET Imaging Study of a Schizophrenia Endophenotype

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DESCRIPTION (provided by applicant): Schizophrenia has a significant genetic risk. However, the specific genes that contribute to the disease phenotype have not been identified. Our alternative approach is to simplify the problem by using well-defined neurophysiological/cognitive traits that have increased genetic component and are expected to mark sub- components of disease risk and hence, specific molecular pathways between gene variants and translated protein/function8. Smooth pursuit eye movement (SPEM, also called eye tracking) abnormality is an established biological marker for schizophrenia. SPEM deficits have been consistently reproduced in over 60 studies of schizophrenia, with few negative results9. Focusing on SPEM can potentially provide new insights into the etiopathophysiology of schizophrenia. The challenge is to decompose this phenotype into its elemental molecular components in order to determine the paths leading from genes to signaling pathways to behaviors, and to schizophrenia. Studies suggest that deficits in predictive pursuit gain (a subcomponent of SPEM) may underlie the eye tracking impairment in schizophrenia patients and their first-degree relatives. The predictive pursuit gain measure is more sensitive in defining at-risk individuals than traditional SPEM measures10-12. Neuroimaging studies have identified several cortical regions associated with SPEM deficits in schizophrenia. The most consistently replicated finding has been, reduced activation in the frontal eye fields (FEF) during SPEM13-15. Although the FEF is the primary cortical area for the control of SPEM, recent studies have shown that FEF control of SPEM is effected through several descending pathways. This functional neural circuitry of the pursuit system consists of a cortico-striato-pallido-thalamo-cortical loop distributed through the midbrain, temporal, parietal, and prefrontal cortices16-18. Emerging evidence from monkeys and humans has established dense efferent projections from the FEF to the caudate nucleus and substantia nigra, and that these relay stations are critical in the neuromotor and cognitive processes that control predictive pursuit19-21. Thus, the FEF and the caudate are regions of interest in the proposed pilot study. Dysregulation of dopamine signaling, particularly in the prefrontal cortex, is considered to be at the core of several neurocognitive deficits in schizophrenia22. Overlapping components of the predictive pursuit circuitry are modulated by dopaminergic neurotransmission, including the FEF and caudate23;24. This proposal will examine the relationship between eye tracking and the density of the dopamine transporter (DAT) in the FEF and caudate in schizophrenia and healthy controls. A second focus will be on the effect of a functional variable number of tandem repeats (VNTR) polymorphism in the dopamine transporter gene (DAT1) and DAT density in the FEF and caudate. DAT density is measured by the binding potential of the DAT-specific radioligand, [11C]WIN 35,428, during Positron Emission Tomography (PET) scan. The study's approach integrates ex vivo molecular biochemistry, functional genomics, and in vivo neuroimaging methodologies. PUBLIC HEALTH RELEVANCE: A pilot study to examine the relationship between a heritable schizophrenia biomarker (eye tracking), DAT1 genotype, and the dopamine transporter density using PET radiotracer imaging.