Epigenetic modifications in the nervous system and their impact upon cognitive impairments

Epigenetic regulation has been long considered to be a critical mechanism in the control of key aspects of cellular functions such as cell division, growth, and cell fate determination. Exciting recent developments have demonstrated that epigenetic mechanisms can also play necessary roles in the nervous system by regulating, for example, neuronal gene expression, DNA damage, and genome stability. Despite the fact that postmitotic neurons are developmentally less active then dividing cells, epigenetic regulation appears to provide means of both long-lasting and very dynamic regulation of neuronal function. Growing evidence indicates that epigenetic mechanisms in the central nervous system (CNS) are important for regulating not only specific aspects of individual neuronal metabolism but also for maintaining function of neuronal circuits and regulating their behavioral outputs. Multiple reports demonstrated that higher-level cognitive behaviors, such as learning and memory, are subject to a sophisticated epigenetic control, which includes interplay between multiple mechanisms of neuronal chromatin modification. Experiments with animal models have demonstrated that various epigenetic manipulations can affect cognition in different ways, from severe dysfunction to substantial improvement. In humans, epigenetic dysregulation has been known to underlie a number of disorders that are accompanied by mental impairment. Here, we review some of the epigenetic mechanisms that regulate cognition and how their disruption may contribute to cognitive dysfunctions. Due to the fact that histone acetylation and DNA methylation are some of the best-studied and critically important epigenomic modifications our research team has particularly strong expertise in, in this review, we are going to concentrate on histone acetylation, as well as DNA methylation/hydroxymethylation, in the mammalian CNS. Additional epigenetic modifications, not surveyed here, are being discussed in depth in the other review articles in this issue of Neuropharmacology.