Megan Mitchell

Introduction. Depressive disorders are a leading cause of disability worldwide. In the US, prevalence ranges from 5-10% with only half receiving adequate treatment.^1,2 The Brain-Derived Neurotrophic Factor (BDNF) protein induces survival, development, and function of neurons; it plays a role in hippocampal learning and memory.¹ BDNF elevation in patients on antidepressant medications indicates a potential protective feature of the protein.³ DNA methylation of BDNF is hypothesized to play a role in the etiology of depression.^3,4. DNA methylation involves the addition of a methyl group to a DNA cytosine which can impact gene expression. DNA methyltransferases (DNMTs) are likely responsible for the methylation of the BDNF gene.⁴ Methyl-CpG-binding protein 2 (MeCP2) facilitates long-term chromatin condensation of DNA surrounding methylated residues, reducing expression of genes such as BDNF. Methods. Adult rats were classified as Roman Low-Avoidance (RLA) and High-Avoidance (RHA) based on their susceptibility to stress-induced depression.³ Using Western blot, BDNF protein levels were measure and compared between RHA and RLA groups.³ Adult rats were subjected to a spared nerve injury (SNI) procedure known to induce depression in rodents.⁴ A subset of that group was then injected peritoneally with a ketamine solution (10 mg/kg in 1 ml) and sacrificed 21 days after ketamine administration.⁴ DNMT and BDNF protein levels were measured using Western Blot.⁴ BDNF knockout mice were injected with ketamine (5 mg/kg) and then sacrificed 7 days later.⁵ Hippocampal MeCP2 expression was measured by Western Blot.⁵ Results. BDNF levels were lower in the hippocampus of depression vulnerable (RLA) rats.³ Elevated DNMT expression in rodent hippocampi was correlated with reduced BDNF expression.⁴ Ketamine was found to reverse the increase of DNMTs in SNI rat hippocampi, allowing for an increase in BDNF expression.⁴ MeCP2 was found to be phosphorylated, and thus, inactivated, 7 days after ketamine administration, preventing chromatin condensation of BDNF and increasing its expression in the hippocampus.⁵ Conclusions. Higher levels of BDNF exert protective effects against symptoms of depression.² Repression of BDNF expression involves addition of a methyl group to specific nucleotides by DNMTs.⁴ Methylated residues then undergo chromatin condensation; this is facilitated in part by MeCP2.⁵ This process reduces BDNF expression in the hippocampus.⁵ Ketamine increases BDNF expression through repression of DNMTs and MeCP2.^4,5 Though further research is needed, early studies suggest that ketamine may be a potential treatment for major depressive disorder.^3,4,5

1. McCarron RM, Shapiro B, Rawles J, Luo J. Depression. Ann Intern Med. 2021;174(5):ITC65-ITC80. doi:10.7326/AITC202105180
2. Watkins SC, Sibille E. The Role of Dendritic Brain-Derived Neurotrophic Factor Transcripts on Altered Inhibitory Circuitry in Depression. Biol Psychiatry. 2019;85(6):517-526. doi:10.1016/j.biopsych.2018.09.026
3. Serra MP, Poddighe L, Boi M, et al. Expression of BDNF and trkB in the hippocampus of a rat genetic model of vulnerability (Roman low-avoidance) and resistance (Roman high-avoidance) to stress-induced depression. Brain Behav. 2017;7(10):e00861. Published 2017 Oct 23. doi:10.1002/brb3.861
4. Liu R, Wu XM, He X, et al. Contribution of DNA methyltransferases to spared nerve injury induced depression partially through epigenetically repressing Bdnf in hippocampus: Reversal by ketamine. Pharmacol Biochem Behav. 2021;200:173079. doi:10.1016/j.pbb.2020.173079
5. Kim JW, Autry AE, Na ES, et al. Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation. Nat Neurosci. 2021;24(8):1100-1109. doi:10.1038/s41593-021-00868-8