Genetic analysis of Htr2c RNA editing in amygdala

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DESCRIPTION (provided by applicant): Htr2c RNA editing alters the potential contribution of 5-HT2C receptors to brain function by producing up to 24 receptor isoforms with different signal transduction properties. Htr2c RNA editing is an important endophenotype for serotonergic function and psychiatric disease, and understanding the genetic etiology of this variation is an important goal. Pharmacological manipulations implicate the cognate ligand serotonin (5-HT) in the regulation of RNA edited 5-HT2C receptors. Inbred mouse strain differences in both serotonin and RNA editing implicate genetic sources of variation. Two single nucleotide polymoprhisms are known to affect serotonergic function in mice. Aims 1, 2, and 3 make use of a balanced factorial table of 40 BXD recombinant inbred lines of mice that represent every two-allele combination of the SNPs Tph2:Pro447Arg and Slc6a4:Glu39Gly. Because the genetic background of the BXD RI lines has been randomized by breeding, this panel of mice in essence performs as a virtual double congenic for two important functional SNPs in the genes for tryptophan hydroxylase and the serotonin transporter. Aim 1 tests the candidacy of these SNPs as quantitative trait nucleotides (QTNs) affecting Htr2c RNA editing profiles. Aim 2 uses genome-wide QTL mapping to explore more broadly other genetic loci that may influence Htr2c RNA editing profiles. Aim 3 proposes to explore behavioral and transcriptome correlates of Htr2c RNA editing. The mouse brain region of investigation is the amygdala, which is rich in 5-HT2C receptors and plays important functional roles in stress, anxiety, fear, and emotional learning and memory. In humans, the amygdala appears to function in related psychological disorders. The serotonin 2C receptor is a focus of mental health research. This proposal aims to discover genetic causes and behavioral correlates of variation in RNA that codes for up to 24 functionally different protein isoforms of the serotonin 2C receptor. The brain region of investigation is the amygdala, which is rich in serotonin 2C receptors and plays important roles in anxiety disorders and depression.