"Transcriptional Regulation of Serotonergic Genes"

The serotonergic system plays a key role in the modulation of mood, emotion, sleep and appetite and consequently is implicated in the control of a plethora of functions of the central nervous system both under physiological conditions and disease states. As such, dysfunction in serotonergic neurotransmission has been implicated in the pathogenesis of schizophrenia, depression, and anxiety. Classical as well as modern antidepressant drugs appear to modulate 5-HT neurotransmission by blocking its reuptake into the pre-synaptic terminal. Given the importance of serotonin and the role genes in the serotonin biosynthetic pathway play in its regulation, there is now mounting evidence that variations (single nucleotide polymorphisms, SNP) both in the coding and regulatory regions of these genes are becoming important predictors of response to drug treatment. Variations have been found in the recently identified brain isoform of tryptophan hydroxylase (TPH2), the rate-limiting enzyme in the biosynthesis of serotonin, the serotonin transporter, and the serotonin-1A receptor. Gene expression is controlled to a large extent at the level of transcription and every gene with a phenotypic impact has regulatory sequences that in conjunction with the expression and activity of proteins encoded elsewhere (transcription and accessory factors), regulate where expression occurs, at what level and under what environmental conditions and in which cells or tissues. The goal of this research is to study the transcriptional regulation of serotonin genes and examine through extensive genotyping the influence of various SNPs on transcription and also to confirm the presence and distribution and functional relevance of these SNPs in our cohorts of depressed and control subjects. Identifying transcriptional mechanisms and the role SNPs play may help to elucidate novel targets for treatment of debilitating mental illness.

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