Epigenetic mechanisms in mood disorders: targeting neuroplasticity

Abstract

Developing novel therapeutics and diagnostic tools based upon an understanding of neuroplasticity is critical in order to improve the treatment and ultimately the prevention of a broad range of nervous system disorders. In the case of mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BPD), where diagnoses are based solely on nosology rather than pathophysiology, there exists a clear unmet medical need to advance our understanding of the underlying molecular mechanisms and to develop fundamentally new mechanism experimental medicines with improved efficacy. In this context, recent preclinical molecular, cellular, and behavioral findings have begun to reveal the importance of epigenetic mechanisms that alter chromatin structure and dynamically regulate patterns of gene expression that may play a critical role in the pathophysiology of mood disorders. Here, we will review recent advances involving the use of animal models in combination with genetic and pharmacological probes to dissect the underlying molecular mechanisms and neurobiological consequence of targeting this chromatin-mediated neuroplasticity. We discuss evidence for the direct and indirect effects of mood stabilizers, antidepressants, and antipsychotics, among their many other effects, on chromatin-modifying enzymes and on the epigenetic state of defined genomic loci, in defined cell types and in specific regions of the brain. These data, as well as findings from patient-derived tissue, have also begun to reveal alterations of epigenetic mechanisms in the pathophysiology and treatment of mood disorders. We summarize growing evidence supporting the notion that selectively targeting chromatin-modifying complexes, including those containing histone deacetylases (HDACs), provides a means to reversibly alter the acetylation state of neuronal chromatin and beneficially impact neuronal activity-regulated gene transcription and mood-related behaviors. Looking beyond current knowledge, we discuss how high-resolution, whole-genome methodologies, such as RNA-sequencing (RNA-Seq) for transcriptome analysis and chromatin immunoprecipitation-sequencing (ChIP-Seq) for analyzing genome-wide occupancy of chromatin-associated factors, are beginning to provide an unprecedented view of both specific genomic loci as well as global properties of chromatin in the nervous system. These methodologies when applied to the characterization of model systems, including those of patient-derived induced pluripotent cell (iPSC) and induced neurons (iNs), will greatly shape our understanding of epigenetic mechanisms and the impact of genetic variation on the regulatory regions of the human genome that can affect neuroplasticity. Finally, we point out critical unanswered questions and areas where additional data are needed in order to better understand the potential to target mechanisms of chromatin-mediated neuroplasticity for novel treatments of mood and other psychiatric disorders.

Keywords: chromatin; epigenetics; experimental medicine; mood disorders; neuroplasticity.

Figure 1. Convergence of pathways involved in the epigenetic regulation of learning and memory with stress responses that may mediate the long-term pathophysiological effects of stress in chromatin-mediated neuroplasticity

Stimuli (I) such as glutamate and glucocorticods released as response of the physiological response to stress and other experiences lead to the activation of both synaptic receptors (II) and intracellular signaling pathways (III) that include the MEK-ERK-MSK cascade involved in phosphorylation of histone H3, ERK-mediated activation of the histone acetyltransferase CBP as part of the chromatin-modifying complexes (IV) that lead to recruitment of additional chromatin-remodeling complexes (v) that alter chromatin structure (V) and lead in turn to altered gene expression states, as well as activation of nuclear hormone receptors, such as the glucocorticoid receptor (GR). Besides HATs and phosphorylation, the structure of chromatin is altered through deacetylation by HDACs, methylation by lysine methyltransferase (KMTs), demethylation by lysine demethylases (KDMs), which depending on the amino acid side chain and context can lead to activation or repression of transcription due to the alteration of charge of the histone tail but also interactions with various protein domains that bind to modified histone residues. Reversible DNA methylation by DNMTs further interacts with chromatin-modification complexes and transcription factors. HDAC6, a cytoplasmic deacetylase that deacetylases the chaperone Hsp90 facilitates the ligand binding, nuclear translocation, and transcriptional activation of GR. Both the inhibition of Class I HDACs (HDAC/1/2/3) and the Class IIb HDAC6 with prototypical HDAC inhibitors, such as MS-275 and NCT-14b, respectively, and have been shown to have antidepressant-like behavioral effects providing evidence that these enzymes normally function as ‘mood suppressors’ that govern susceptibility and resilience to stress induced pathophysiology.

Figure 2. Prototypical small-molecule probes targeting epigenetic mechanisms with effects on moodrelated behavior

Lysine deacetylase inhibitors affect nuclear and non-nuclear members of the zinc-dependent family of histone deacetylases (HDACs). DNMT inhibitors affect DNA methylation through integration into DNA (zebularine) or direct inhibition of DNMTs (RG108).