Patients with schizophrenia have difficulty screening out irrelevant stimuli, and often have the experience of sensory flooding. These "gating deficits" may contribute to the thought disorder, cognitive fragmentation and hallucinations which are so debilitating to these individuals. The acoustic startle response is a reflex contraction of the skeletal muscles in response to a sudden acoustic stimulus. It occurs across mammalian species and can be easily measured. The modulation of this reflex by a preliminary nonstartling stimulus is termed prepulse inhibition of acoustic startle (PPI), a paradigm which is used as an operational measure of sensorimotor gating. In consonance with the schizophrenia symptoms that are suggestive of gating deficits, many patients with schizophrenia have deficits in PPI when compared to healthy controls. The brain regions that modulate PPI include the hippocampus and prefrontal cortex, areas that are implicated as being abnormal in schizophrenia. Our prior work and work from other labs suggests that PPI impairment in schizophrenia does not improve with treatment and hence may be a trait related abnormality. Work from our current funding period supports our original hypothesis, namely that impaired PPI exhibits familial association. Specifically, we are finding that PPI in first degree family members of subjects with schizophrenia is impaired. Further work is needed in order to establish that PPI impairment is heritable.

An endophenotype is a measurable trait or phenotype detectable by a biological test. Using an endophenotype rather than presence or absence of disease is a powerful tool in the study of diseases with complex polygenic etiologies such as schizophrenia. Progress in the genetics of schizophrenia is greatly confounded by the difficulty in identifying individuals who carry genes contributing to schizophrenia. Incomplete penetrance and the fact that both heritable and environmental factors interact to produce the disease add to this difficulty. This means that some individuals carrying vulnerability genes for schizophrenia who fail to exhibit robust symptoms will be classified erroneously as unaffected in genetic studies, confounding attempts to reliably define the heritable phenotype. The phenomenon of incomplete penetrance is exhibited by the finding that the risk of schizophrenia is the same for children of affected and nonaffected monozygotic twins. The polygenic etiology of schizophrenia makes it unlikely that a pooled sample of individuals defined by the presence of schizophrenia will greatly overlap in the vulnerability genes that they carry. The goal of the endophenotype approach is to narrow the defined phenotype so that a more homogeneous genotype is expected, making it much more fruitful and to conduct genetic studies.

We hypothesize that impaired PPI will prove to be a heritable endophenotype in schizophrenia. Based on our work accomplished during the current funding period, we now propose to further develop this line of research by conducting a heritability analysis of PPI. Our field is greatly in need of this work as a prelude to endophenotype-based genetic studies. We will accomplish our important goal by collecting and characterizing a cohort of healthy controls and their families, and by expanding our sample of schizophrenia subjects and their families. We will collect diagnostic, symptom, cognitive, pedigree, and PPI data all subjects, and will collect blood and extract DNA for future genetic analyses. We will use a family based strategy to investigate the pattern and degree of heritability of impaired PPI in families of schizophrenia and control probands.

This project will provide the necessary next step in advancing the use of impaired PPI as a powerful tool for the discovery of vulnerability genes contributing to schizophrenia. Currently available treatments for this devastating disorder are sadly inadequate. Our medications are virtually ineffective for a subset of our patients. The discovery of vulnerability genes and of a method for biological subtyping of patients will allow our field to develop genetically informed new treatments that specifically target particular subtypes of patients. This approach is our best hope for bringing relief to patients suffering from this disease.