Molecular Genetics of the Serotonin System

Case Western Reserve University, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): The long term objective of this study is to understand the genetic factors controlling the development and function of the serotonergic system in the human brain. The proposed experiments will test the hypothesis that there is a conserved genetic program controlling the human and the mouse serotonin (5-HT) system, specifically focusing on the transcription factor Pet-1. Molecular cloning, transgenic mouse production, histology, reverse transcriptase Real-Time PCR, high performance liquid chromatography, and behavioral testing will be the methods used in the three proposed specific aims. The organization of the human Bacterial Artificial Chromosome (BAC) containing Fev, the human Pet-1 homologue, will be determined and then the BAC will be used to generate transgenic mouse lines. The transgene (TG) positive, Pet-1 null mice will be examined to determine hPet-1's functionality in the mouse 5-HT system, specifically looking at 5-HT levels in the brain, and at the expression of tryptophan hydroxylase (the enzyme that synthesizes 5-HT) and the serotonin transporter (SERT). The anxiety and aggression levels of the TG+ mice will be evaluated using behavioral assays such as the open field test, elevated plus maze, and the resident intruder assay.