DNA Methylation and the Opposing NMDAR Dysfunction in Schizophrenia and Major Depression Disorders: a Converging Model for the Therapeutic Effects of Psychedelic Compounds in the Treatment of Psychiatric Illness

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2023 Sep 7

PMID 37679470

Authors

L Taylor Flynn

Wen-Jun Gao

Affiliations

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Abstract

Psychedelic compounds are being increasingly explored as a potential therapeutic option for treating several psychiatric conditions, despite relatively little being known about their mechanism of action. One such possible mechanism, DNA methylation, is a process of epigenetic regulation that changes gene expression via chemical modification of nitrogenous bases. DNA methylation has been implicated in the pathophysiology of several psychiatric conditions, including schizophrenia (SZ) and major depressive disorder (MDD). In this review, we propose alterations to DNA methylation as a converging model for the therapeutic effects of psychedelic compounds, highlighting the N-methyl D-aspartate receptor (NMDAR), a crucial mediator of synaptic plasticity with known dysfunction in both diseases, as an example and anchoring point. We review the established evidence relating aberrant DNA methylation to NMDAR dysfunction in SZ and MDD and provide a model asserting that psychedelic substances may act through an epigenetic mechanism to provide therapeutic effects in the context of these disorders.

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References

Delint-Ramirez I, Salcedo-Tello P, Bermudez-Rattoni F . Spatial memory formation induces recruitment of NMDA receptor and PSD-95 to synaptic lipid rafts. J Neurochem. 2008; 106(4):1658-68. DOI: 10.1111/j.1471-4159.2008.05523.x. View

Kegeles L, Abi-Dargham A, Zea-Ponce Y, Mann J, van Heertum R, Cooper T . Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry. 2000; 48(7):627-40. DOI: 10.1016/s0006-3223(00)00976-8. View

Uchida S, Hara K, Kobayashi A, Otsuki K, Yamagata H, Hobara T . Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events. Neuron. 2011; 69(2):359-72. DOI: 10.1016/j.neuron.2010.12.023. View

Gulchina Y, Xu S, Snyder M, Elefant F, Gao W . Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia. J Neurochem. 2017; 143(3):320-333. PMC: 5653427. DOI: 10.1111/jnc.14101. View

Kumar S, Cheng X, Klimasauskas S, Mi S, Posfai J, Roberts R . The DNA (cytosine-5) methyltransferases. Nucleic Acids Res. 1994; 22(1):1-10. PMC: 307737. DOI: 10.1093/nar/22.1.1. View

Adell A . Brain NMDA Receptors in Schizophrenia and Depression. Biomolecules. 2020; 10(6). PMC: 7355879. DOI: 10.3390/biom10060947. View

Bartanusz V, Aubry J, Pagliusi S, Jezova D, Baffi J, Kiss J . Stress-induced changes in messenger RNA levels of N-methyl-D-aspartate and AMPA receptor subunits in selected regions of the rat hippocampus and hypothalamus. Neuroscience. 1995; 66(2):247-52. DOI: 10.1016/0306-4522(95)00084-v. View

Ly C, Greb A, Cameron L, Wong J, Barragan E, Wilson P . Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018; 23(11):3170-3182. PMC: 6082376. DOI: 10.1016/j.celrep.2018.05.022. View

Boyes J, Bird A . Repression of genes by DNA methylation depends on CpG density and promoter strength: evidence for involvement of a methyl-CpG binding protein. EMBO J. 1992; 11(1):327-33. PMC: 556453. DOI: 10.1002/j.1460-2075.1992.tb05055.x. View

10.

Inserra A, Campanale A, Cheishvili D, Dymov S, Wong A, Marcal N . Modulation of DNA methylation and protein expression in the prefrontal cortex by repeated administration of D-lysergic acid diethylamide (LSD): Impact on neurotropic, neurotrophic, and neuroplasticity signaling. Prog Neuropsychopharmacol Biol Psychiatry. 2022; 119:110594. DOI: 10.1016/j.pnpbp.2022.110594. View

11.

Weder N, Zhang H, Jensen K, Yang B, Simen A, Jackowski A . Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. J Am Acad Child Adolesc Psychiatry. 2014; 53(4):417-24.e5. PMC: 4126411. DOI: 10.1016/j.jaac.2013.12.025. View

12.

Aran D, Toperoff G, Rosenberg M, Hellman A . Replication timing-related and gene body-specific methylation of active human genes. Hum Mol Genet. 2010; 20(4):670-80. DOI: 10.1093/hmg/ddq513. View

13.

Clements J, Westbrook G . Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor. Neuron. 1991; 7(4):605-13. DOI: 10.1016/0896-6273(91)90373-8. View

14.

Dong B, Chen H, Sakata K . BDNF deficiency and enriched environment treatment affect neurotransmitter gene expression differently across ages. J Neurochem. 2020; 154(1):41-55. PMC: 7319906. DOI: 10.1111/jnc.15017. View

15.

Bennett M, Lagopoulos J . Stress and trauma: BDNF control of dendritic-spine formation and regression. Prog Neurobiol. 2013; 112:80-99. DOI: 10.1016/j.pneurobio.2013.10.005. View

16.

Bonaventura J, Lam S, Carlton M, Boehm M, Gomez J, Solis O . Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry. 2021; 26(11):6704-6722. PMC: 8517038. DOI: 10.1038/s41380-021-01093-2. View

17.

Bird A . DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res. 1980; 8(7):1499-504. PMC: 324012. DOI: 10.1093/nar/8.7.1499. View

18.

Ferland C, Schrader L . Regulation of histone acetylation in the hippocampus of chronically stressed rats: a potential role of sirtuins. Neuroscience. 2010; 174:104-14. PMC: 3020273. DOI: 10.1016/j.neuroscience.2010.10.077. View

19.

Minichiello L . TrkB signalling pathways in LTP and learning. Nat Rev Neurosci. 2009; 10(12):850-60. DOI: 10.1038/nrn2738. View

20.

Erreger K, Dravid S, Banke T, Wyllie D, Traynelis S . Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. J Physiol. 2005; 563(Pt 2):345-58. PMC: 1665591. DOI: 10.1113/jphysiol.2004.080028. View