Gene network of dopamine receptor type 2 (Drd2) in addiction

Authors

• L Guerri
• L Bobbs
• A Meyers
• V Alvarez
• D Goldman

Abstract

BACKGROUND Low availability of type-2 dopamine receptors (D2Rs) in the striatum has been observed in a wide range of conditions associated with impaired decision-making, such as addiction, obesity and ADHD. Two neuronal populations accounts for most of D2R expression in the striatum: Medium Spiny Neurons of the “indirect pathway” (iMSNs) and the projections (auto-receptors) of dopamine neurons from VTA. However, neither the causes, the functional consequences nor the cellular component of this downregulation are well understood. METHODS To study the downstream effects of D2R gene (Drd2) downregulation and its gene network, we purify the whole transcriptome of iMSNs mice with either WT or low level (het) of D2R expression. This is achieved by conditionally driving both the expression of the Translating Ribosome Affinity Purification (TRAP) system and a floxed Drd2, in iMSNs. TRAP positive (iMSNs) and negative (striatum depleted of iMSNs) fractions were analyzed by RNAseq. RESULTS and PERSPECTIVES The comparison of TRAP positive and negative fractions by RNAseq shows a successful enrichment on the expected cell type markers. However, the transcriptome analysis of iMSNs from D2R wt and het mice shows a strong technical batch effect driven by the TRAP batch isolation. The analysis of differential gene expression, taking into account the batch effect, shows enrichment in relevant pathways related to neural signaling. A lists of 30 candidate genes is currently being evaluated by qPCR. In parallel a new analysis correcting for the batch effect is being performed. Validated targets will be studied at protein level, as well as targeted for behavioral studies in the context of cocaine exposure and self-administration paradigm. The comparison of the two groups: D2R wt and het, will allow us to identify the gene network that is affected by D2R downregulation in addiction, and possible new targets for treatment.

Scientific Focus Area: Genetics and Genomics

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