Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

J Psychiatry Neurosci 2019;44(3):164-176 | Full Text | PDF

Paul R. Albert, PhD; Brice Le François, PhD; Faranak Vahid-Ansari, PhD

Major depression and anxiety are highly prevalent and involve chronic dysregulation of serotonin, but they remain poorly understood. Here, we review novel transcriptional (genetic, epigenetic) and posttranscriptional (microRNA, alternative splicing) mechanisms implicated in mental illness, focusing on a key serotonin-related regulator, the serotonin 1A (5-HT1A) receptor. Functional single-nucleotide polymorphisms and stress-induced DNA methylation of the 5-HT1A promoter converge to differentially alter pre- and postsynaptic 5-HT1A receptor expression associated with major depression and reduced therapeutic response to serotonergic antidepressants. Major depression is also associated with altered levels of splice factors and microRNA, posttranscriptional mechanisms that regulate RNA stability. The human 5-HT1A 3′-untranslated region is alternatively spliced, removing microRNA sites and increasing 5-HT1A expression, which is reduced in major depression and may be genotype-dependent. Thus, the 5-HT1A receptor gene illustrates the convergence of genetic, epigenetic and posttranscriptional mechanisms in gene expression, neurodevelopment and neuroplasticity, and major depression. Understanding gene regulatory mechanisms could enhance the detection, categorization and personalized treatment of major depression.

Submitted Nov. 1, 2018; Revised Dec. 10, 2018; Accepted Dec. 21, 2018; Published online Feb. 26, 2019

Acknowledgements: The authors’ research was supported in part by grants from the Canadian Institutes of Health Research to P. Albert.

Affiliations: From the Department of Neuroscience, Ottawa Hospital Research Institute, UOttawa Brain and Mind Research Institute, Ottawa, Ont., Canada.

Competing interests: P. Albert sits on the JPN editorial board. He was not involved in the decision-making on this manuscript. No other competing interests declared.

Contributors: All authors reviewed and interpreted the literature. P. Albert wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.180209

Correspondence to: P.R. Albert, OHRI (Neuroscience), UOttawa Brain and Mind Research Institute, 451 Smyth Rd, Ottawa ON K1H 8M5;