Taylor Shantz

Background: Major Depressive Disorder (MDD) is a mental health disorder characterized by diminished quality of life and limitations on psychological and social functioning.¹ MDD is an illness affecting one in five people in their lifetime and is the greatest form of depression diagnosed that involves recurrent depressive episodes.¹ The influences of biological and psychosocial factors to the etiology of depression are variable which is why they are of importance in clinical studies.¹ Serotonergic (5-HT) neurons project from the raphe nuclei and touch multiple systems. The dorsal raphe nucleus (DRN) composes 85% of the serotonergic neurons in the central nervous system and projects to emotion-related brain regions.^4,5 The SERT transporter is encoded by the SLC6A4 gene which regulates the extracellular serotonin levels, with its upregulation involving reuptake of serotonin from the synaptic cleft so that it can be repackaged or metabolized. This indicates that increased expression of SLC6A4 will reduce the amount of serotonin in the synaptic cleft, and this dysregulation of serotonin levels has been the basis for the monoaminergic theory of depression.^4,8 The monoaminergic theory of depression suggests that a reduction in hippocampal neurogenesis is involved in the pathogenesis of depression.⁸ Epigenetic mechanisms, such as DNA methylation, of the SLC6A4 gene have been associated with depression.⁷

Objective: In this narrative review, we explored the epigenetic mechanisms by which SLC6A4 alterations related to depression.

Search Methods: Online search utilizing the PubMed database was performed to analyze articles from 2017 to 2023 with the following keywords: “depression”, “SLC6A4”, “serotonin”, “methylation”

Results: Studies showed that loss of function in SERT corresponded to a loss of volume in several regions of the brain of mice models that had projections connected to the dorsal raphe nucleus. It is inferred that the depleted SERT in the dorsal raphe nucleus led to the reduced volume in the adjacent brain regions through the serotonergic projection.⁴ A further examination of the DRN and its relationship to depression, a study showed that 4 weeks of regular treadmill running in a sample of rats enhanced neuronal activity in the DRN which correlated to a reduction in depressive-like behaviors, indicating that long-term repeated exercise can induce an antidepressant role through modulation of DRN neuronal activity.⁵ In another study examining the effects of cessation of long-term exercise on depression and hippocampal gene expression in mice, there was a significant difference between the exercise cessation groups immobility time which was used to measure depression and there was also an increased expression of Slc6a4 gene in this group.⁸ With the SERT transporter playing a major role in the regulation of serotonergic pathways, the first-line antidepressants prescribed are selective serotonin reuptake inhibitors (SSRIs).⁷ A clinical trial showed that after treatment with SSRIs, patients’ average depression score was reduced and there was an associated decline in levels of DNA damage.⁹

Conclusions: The mechanisms of depression are still of concern, but there are studies showing the role of the serotonin transporter gene, SLC6A4, playing a key role. Gene modifications such as DNA methylation of SLC6A4 have been correlated with increased depression. With more studies about the basic underlying mechanisms and the directionality of the associations between epigenetic modifications and depression, it may lead to the discovery of new and more effective treatment options.

Works Cited:

1. Malhi GS, Mann JJ. Depression. Lancet. 2018;392(10161):2299-2312. doi:10.1016/S0140-6736(18)31948-2
2. Webb LM, Phillips KE, Ho MC, Veldic M, Blacker CJ. The Relationship between DNA Methylation and Antidepressant Medications: A Systematic Review. Int J Mol Sci. 2020;21(3):826. Published 2020 Jan 28. doi:10.3390/ijms21030826
3. Park C, Rosenblat JD, Brietzke E, et al. Stress, epigenetics and depression: A systematic review. Neurosci Biobehav Rev. 2019;102:139-152. doi:10.1016/j.neubiorev.2019.04.010
4. Ellegood J, Yee Y, Kerr TM, et al. Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging. Mol Autism. 2018;9:24. Published 2018 Apr 10. doi:10.1186/s13229-018-0210-z
5. Nishii A, Amemiya S, Kubota N, Nishijima T, Kita I. Adaptive Changes in the Sensitivity of the Dorsal Raphe and Hypothalamic Paraventricular Nuclei to Acute Exercise, and Hippocampal Neurogenesis May Contribute to the Antidepressant Effect of Regular Treadmill Running in Rats. Front Behav Neurosci. 2017;11:235. Published 2017 Nov 24. doi:10.3389/fnbeh.2017.00235
6. Shao QY, You F, Zhang YH, et al. CSF miR-16 expression and its association with miR-16 and serotonin transporter in the raphe of a rat model of depression. J Affect Disord. 2018;238:609-614. doi:10.1016/j.jad.2018.06.034
7. Palma-Gudiel H, Peralta V, Deuschle M, Navarro V, Fañanás L. Epigenetics-by-sex interaction for somatization conferred by methylation at the promoter region of SLC6A4 gene. Prog Neuropsychopharmacol Biol Psychiatry. 2019;89:125-131. doi:10.1016/j.pnpbp.2018.09.002
8. Morgan JA, Singhal G, Corrigan F, et al. Ceasing exercise induces depression-like, anxiety-like, and impaired cognitive-like behaviours and altered hippocampal gene expression. Brain Res Bull. 2019;148:118-130. doi:10.1016/j.brainresbull.2019.02.014
9. Ahmadimanesh M, Abbaszadegan MR, Morshedi Rad D, et al. Effects of selective serotonin reuptake inhibitors on DNA damage in patients with depression. J Psychopharmacol. 2019;33(11):1364-1376. doi:10.1177/0269881119874461