Catherine Nettesheim


Summer Research Description: Transcripts encoding the 2C-subtype of the serotonin (5HT2C) receptor can be modified via by an editing post-transcriptional modification process  in which five genomically-encoded adenosines are converted to inosine within the RNA to encode -to-inosine conversions can generate up to 24 protein isoforms that differ in three amino acids. The fully-edited (VGV) isoform of the 5HT2C receptor, encoding valine, glycine and valine at amino acid positions 157, 159 and 161 respectively, exhibits reduced constitutive activity and decreased G-protein coupling efficacy in comparison to the genomically-encoded (INI) isoform. The reduced signaling properties of more highly edited isoforms has led to the idea that editing may represent a homeostatic mechanism that stabilizes 5HT2C  signaling in response to changing serotonergic input. In this study, we will treat adult, C57BL/6 mice with parachlorophenylalanine (pCPA), an inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis. The distribution profile of editing in six regions (hypothalamus, hippocampus, olfactory bulb, striatum, cortex, and cerebellum) will be compared between pCPA- and saline- treated animals using a deep sequencing -based strategytechnique. Reduced serotonin biosynthesis, induced by the pCPA treatment, is expected to decrease editing of 5HT2C mRNAs to generate isoforms with increased signaling activity to maintain a constant serotonergic tone, supporting a role for editing in the . This observation would provide evidence for the function of RNA editing in the maintenance of 5HT2C signaling.