Project Summary

Noboru Hiroi, Ph.D., (Independent Investigator 2006) of Albert Einstein College of Medicine of Yeshiva University, notes that the human chromosome 22q11.2 is thought to contain genes whose abnormalities heighten the susceptibility to neuropsychiatric disorders and behavioral defects, including schizophrenia. To identify chromosomal segments within 22q11.2 that confer a heightened susceptibility to these disorders, Dr. Hiroi has initiated analysis of distinct segments of the chromosome. He will examine the functional role of a segment of the chromosome in behaviors considered to be measurable indicators of schizophrenia. This chromosomal segment contains thioredoxin reductase 2 (TXNRD2), catechol-O-methyl-transferase (COMT) and armadillo repeat gene deletes in velocardiofacial syndrome (ARVCF). Dr. Hiroi chose this segment for two reasons: haplotype analysis suggests that this particular segment contributes to schizophrenia and each of the three genes plays a role in functions that are implicated in schizophrenia. COMT regulates dopamine levels in the brain. TXNRD2 and ARVCF are critical for cell-cell communication and developmental processes. He will initially delineate the extent to which over-expression of this chromosomal segment contributes to indicators of schizophrenia, such as abnormalities in prepulse inhibition, habituation to acoustic stimuli, and social interaction in transgenic mice. He will then ascertain the role of heightened COMT enzymatic activity in behavioral deficits in the aforementioned tasks using the selective COMT inhibitor tolcapone to normalize COMT levels in transgenic mice. These two sets of experiments will ascertain the role of this chromosomal segment and a high level of COMT activity in endophenotypes of schizophrenia. Moreover, this mouse model will provide an opportunity to develop novel therapeutic options to treat the cognitive deficits of schizophrenia.

Program Area: MULTIPLE FOCUS\Mood Disorders/Schizophrenia

Search Again