Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders

Abstract

Epigenetic chromatin remodeling and modifications of DNA represent central mechanisms for regulation of gene expression during brain development and in memory formation. Emerging evidence implicates epigenetic modifications in disorders of synaptic plasticity and cognition. This review focuses on recent findings that HDAC inhibitors can ameliorate deficits in synaptic plasticity, cognition, and stress-related behaviors in a wide range of neurologic and psychiatric disorders including Huntington's disease, Parkinson's disease, anxiety and mood disorders, Rubinstein-Taybi syndrome, and Rett syndrome. These agents may prove useful in the clinic for the treatment of the cognitive impairments that are central elements of many neurodevelopmental, neurological, and psychiatric disorders.

Figure 1. Scheme showing that neurological and psychiatric disorders involve epigenetic modifications of key neuronal genes and intervention by HDAC inhibitors

Neurodegenerative diseases (Huntington’s disease, Parkinson’s disease and ischemia), psychiatric disorders (depression, stress and anxiety) and neurodevelopmental disorders (Rubinstein-Taybi syndrome and Fragile X syndrome) can involve aberrant acetylation and methylation of histones and/or DNA methylation. These epigenetic modifications can be influenced by experience and determine the transcriptional state of regulatory genes critical to synaptic plasticity, cognition and mood. Histone deacetylase inhibitors such as valproic acid (VPA) and trichostatin A (TSA) inhibit the activity of HDACs, shifting the balance toward active transcription of neuronal genes and amelioration of plasticity and cognitive deficits. Adapted from [55]. Inset adapted from [8].