Attenuation of Htr2b expression selectively alters a dopaminergic gene network in the midbrain of heterozygous knock-out mice

Authors

• R Panarsky
• C Hodgkinson
• K Schuebel
• Q Yuan
• A Holmes
• D Goldman

Abstract

It has been shown that carriers of a nonsense mutation in the serotonin 2B receptor gene (HTR2B) display higher impulsivity and aggression (Bevilacqua et all, Nature 2010). However the mechanism by which the 5-HT2B receptor modulates behavior remains unclear. In the present study we analyzed, using total RNA-Seq approach, transcriptomes of midbrain and prefrontal cortex of heterozygous Htr2b knockout mice and of the parental strain, in hope to identify a pattern of change in global gene expression caused by the mutation. Total-RNA was isolated from the two brain regions of six male heterozygous Htr2b knockout and from six male wild-type animals. rRNA was depleted and the libraries sequenced on a 5500W DNA analysis system (Life Technologies). Average coverage for each library was 21M mapped reads. The RNA-Seq data was analyzed in CLC Bio Workbook and statistical significance determined by empirical analysis of DGE (common dispersion). Comparison of the wild-type and heterozygous knockout mice showed significant upregulation of four genes Drd1a, Adora2a, Adcy5, Ppp1r1b (180%, 300%, 70% and 150% respectively), in the midbrain but not in prefrontal cortex of knockout mice. These RNA-Seq results were validated by qPCR. All four genes are involved in dopamine intrinsic signaling and synaptic plasticity and predicted to contribute to various neuropathological conditions including alcohol and drug addiction. These findings indicate that 5-HT2B receptor might have a role in the maintenance of serotonergic-dopaminergic crosstalk in the midbrain and its reduced levels trigger compensatory mechanisms in dopaminergic neurons which lead eventually to upregulation of dopaminergic circuitry elements.

Scientific Focus Area: Genetics and Genomics

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