This proposal is a collaborative effort between neurobiologists and geneticists to find a genetically-determined neurobiological factor which is a critical factor in the pathophysiology of schizophrenia. The initial direction comes from studies of sensory gating using the auditory P50 evoked potential wave, which demonstrate that schizophrenics lack the normal ability to suppress this wave in a paired pulsed, conditioning-testing paradigm. This deficit is strongly familial. Project 1 will study the P50 gating deficit and another deficit, abnormal smooth pursuit eye movements, in family pedigrees containing schizophrenia. These neurophysiological abnormalities may be phenotypic expressions of genes conveying risk for schizophrenia. Project 2 will use complementary DNA probes with restriction enzyme fragments and variable tandem repeat sequences to find genetic linkage for these phenotypes. Project 3 will extend the neurobiological understanding of the sensory gating phenotype by examining its physiology in the limbic forebrain of laboratory animals. Project 4 will perform studies, in parallel to the animal studies of Project 3, of the neurobiology in normal and schizophrenic humans, using magneto-encephalography to localize the source of auditory P50 waves in the temporal lobe. Project 5 will perform intraocular transplants of various human fetal limbic brain regions into the anterior chamber of the eye of rats. The transplants will be used for neurophysiological and neuroanatomical studies that would be used for neurophysiological and neuroanatomical studies that would otherwise not be possible in human brain tissue. Some of these fetuses will come from schizophrenic women, so that the neurobiology of normal sensory gating as well as the sensory gating deficit in schizophrenia will be studied at the single neuron level. The five projects will thus combine to characterize the genetics and neurobiology of a brain deficit which is a putative inherited risk factor for schizophrenia.
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