Understanding the Role of COMT Variants in Sensorimotor Gating

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DESCRIPTION (provided by applicant): A single nucleotide polymorphism (SNP), causing a missense mutation of codon 158 Valine to Methionine in the coding region (termed val158met), exists in the human catechol-o-methyltransferase (COMT) gene. This COMT-Met polymorphism is unique for humans and decreases COMT enzymatic activity 40% in prefrontal cortex tissue. This decrease in enzymatic activity can reduce dopamine clearance in the cortex and enhance dopamine signaling. Since evidence supports a reduction in dopamine signaling in prefrontal cortex in schizophrenia patients, the relationship between the COMT gene and schizophrenia has been extensively studied. Association studies of the COMT val158met SNP with schizophrenia risk are inconsistent, however, and support only a small contribution. Given the complexity and overlapping nature of most neuropsychiatric disorders, it is unlikely that a simple gene to complex trait mechanisms can be identified. Instead, it has been suggested that optimally reduced measures of neuropsychiatric function or "endophenotypes" may be more useful than diagnoses to understand genetic contributions to psychiatric disorders such as schizophrenia. Preliminary data indicate that prepulse inhibition is modulated by the COMT gene in both mice and humans. Prepulse inhibition is an operational measure of sensorimotor gating that is deficient in schizophrenia. Little is known about the functional mechanisms underlying COMT val158met effects on this and other schizophrenia endophenotypes. The COMT SNP is ideally suited for modeling in mice as it is a coding region SNP with a well characterized functional effect on the dopamine metabolism pathway, which is relatively conserved between humans and mice. Indeed, "expressing specific human alleles of interest in mice may help elucidate gene/protein regulation and function, providing novel model systems to study human genes related to brain development, physiology, pharmacology, neurochemistry, and behavior" (RFA NH08-050: Mouse Models Containing Human Alleles: Novel Tools to Study Brain Function). In response to this program announcement, two mutant mouse lines will be created, each carrying a human COMT gene with either the Valine or Methionine polymorphism. Studies will test the hypothesis that similar to humans, mice carrying the COMT-Val allele will show poor prepulse inhibition performance compared to mice carrying the COMT-Met allele. This mouse model of COMT val158met polymorphism could play a critical role in the identification of mechanisms of COMT effects on neuropsychiatric endophenotypes such as sensorimotor gating. In the future, this model can aid in examination of COMT gene vulnerability interactions with other genes or environmental factors relevant to schizophrenia and other neuropsychiatric disorders, such as stress, immune challenge, and developmental insult.