RT Journal Article
SR Electronic
T1 Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm
JF Journal of Psychiatry and Neuroscience
JO J Psychiatry Neurosci
FD Canadian Medical Association
SP 164
OP 176
DO 10.1503/jpn.180209
VO 44
IS 3
A1 Paul R. Albert
A1 Brice Le François
A1 Faranak Vahid-Ansari
YR 2019
UL http://jpn.ca/content/44/3/164.abstract
AB 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.