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Nestler et al. (2016) — Epigenetic Basis of Mental Illness

Full citation: Nestler EJ, Peña CJ, Kundakovic M, Mitchell A, Akbarian S. “Epigenetic Basis of Mental Illness.” The Neuroscientist. 2016 Oct;22(5):447–463. doi:10.1177/1073858415608147.

File: raw/nihms745234.pdf

Institution: Icahn School of Medicine at Mount Sinai, Friedman Brain Institute

Summary

A review paper covering epigenetic mechanisms implicated in three major psychiatric syndromes: depression, schizophrenia (SCZ), and bipolar disorder. Draws on both animal models and human postmortem brain studies. Focuses on histone modifications and DNA methylation; explicitly excludes noncoding RNAs and peripheral-tissue-only studies from primary scope.

Core thesis: transcriptional dysregulation driven by aberrant epigenetic regulation is a unifying theme across psychiatric disorders. Environmental factors (especially stress) recruit epigenetic machinery in specific brain regions, producing lasting changes in disease susceptibility.

Key Arguments and Findings

Depression

  • Depression is only ~40% heritable; nongenetic (environmental) factors are critical.
  • HDAC inhibition exerts antidepressant-like effects in rodent stress models (NAc, hippocampus, amygdala, PFC).
  • Chronic social defeat stress downregulates G9a/GLP histone methyltransferases in NAc, reducing H3K9me2 (a repressive mark); this is maladaptive.
  • Fluoxetine partly acts by restoring H3K9me2 at specific gene loci (e.g., Camkiia, Ras).
  • H3K27me3 increases upstream of Rac1 in susceptible mice, reducing Rac1 and altering dendritic spines — corroborated in depressed humans.
  • Dnmt3a upregulated in NAc after chronic social defeat; DNMT inhibitor RG108 has antidepressant effects.
  • Early life adversity (prenatal stress, maternal separation, low maternal care) causes lasting epigenetic changes at Nr3c1 (glucocorticoid receptor), BDNF, Avp, Crf, altering stress reactivity into adulthood.
  • Human postmortem work in depression is sparse; elevated H3K4me3 found at synapsin genes in PFC of depressed patients.

Schizophrenia

  • SCZ primarily studied via postmortem human brain; animal models are limited.
  • RELN (reelin) promoter hypermethylated in PFC in SCZ, associated with reduced reelin expression and elevated DNMT1.
  • SOX10 hypermethylated in PFC; linked to oligodendrocyte dysfunction and myelin abnormalities.
  • GAD1 (GABA synthesis enzyme) shows robust epigenetic dysregulation: excessive repressive DNA and histone methylation, reduced H3K4me3, and weakened 3D chromatin looping enhancing GAD1 promoter in PFC.
  • 3D chromatin architecture changes also found at CACNA1C.
  • HLA genes show altered methylation, implicating neuroinflammation.
  • Mutations in ~50 chromatin regulator genes linked to neurodevelopmental syndromes including rare SCZ forms.

Bipolar Disorder

  • Considerable epigenetic overlap with SCZ.
  • HLA9 shows aberrant methylation in postmortem brain, blood, and sperm of bipolar patients — mechanism unclear.
  • GAD1 altered DNA methylation in hippocampus in bipolar disorder.
  • H3K4 methylation regulators appear among the strongest genetic risk factors for bipolar disorder (GWAS data, Psychiatric Genetics Consortium 2015).

Epigenetic Mechanisms (General)

  • Nucleosome = DNA wrapped around histone octamer (H2A, H2B, H3, H4).
  • Histone modifications: acetylation (generally activating), methylation (context-dependent), phosphorylation.
  • Writers (HATs, HMTs), erasers (HDACs, HDMs), readers (chromatin remodeling proteins).
  • DNA methylation at CpG sites generally repressive; 5hmC (TET-mediated) correlates with activation — most studies do not distinguish 5mC from 5hmC.
  • Histone code hypothesis: sum of modifications at a gene determines epigenetic state (not yet fully decoded).

How This Updates the Wiki

  • Introduces epigenetic regulation as a core mechanism page.
  • Establishes condition pages for depression, schizophrenia, and bipolar disorder with epigenetic framing.
  • Establishes treatment pages for HDAC inhibitors and DNMT inhibitors.
  • Opens two debates: (1) whether epigenetic changes are causal vs. correlational; (2) whether peripheral epigenetic marks reflect brain state.

Limitations Noted by Authors

  • Most studies have not distinguished 5mC from 5hmC.
  • Sex differences are virtually unstudied.
  • Genome-wide epigenetic maps are largely incomplete.
  • Causal direction (epigenetic change → disorder vs. disorder → epigenetic change) is unresolved for most findings.
  • Nearly all SCZ postmortem work focuses on PFC; subcortical regions are understudied.