SIRT1 is a deacetylase involved in DNA repair and genomic stability that was originally identified in non-mammalian model systems as a modulator of longevity. Although it was thought to function in normal brain physiology, it was not known whether SIRT1 participates in higher-order brain functions. Gao et al. now demonstrate such a role for SIRT1: its activation enhances synaptic strength and memory formation. These SIRT1-dependent effects are regulated through a post-transcriptional mechanism involving CREB activation and miR-134 production. This interplay between SIRT1 activation, miR-134 levels and synaptic proteins constitutes a previously unrecognized mechanism of plasticity regulation, and suggests that SIRT1 activation may have therapeutic potential in neurodegenerative diseases involving cognitive impairment. The deacetylase SIRT1 has been suggested to function in normal brain physiology, but it is not known whether it participates in higher-order brain functions. These authors demonstrate a role for SIRT1 in synaptic plasticity and memory formation, with activation enhancing synaptic strength and memory formation. These effects were regulated through a post-transcriptional mechanism involving CREB activation and miR-134 production. This interplay represents another mechanism of plasticity regulation with behavioural consequences. The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies1,2. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.

Histone deacetylase 2 is shown to suppress genes involved in cognitive function epigenetically, potentially opening the door to treatments for Alzheimer’s and other neurodegenerative diseases by developing HDAC2-selective inhibitors. What causes the cognitive decline associated with neurodegenerative diseases is not fully understood. This study reveals a novel epigenetic mechanism by which Alzheimer's-disease-related neurotoxicity reduces the expression of genes necessary for neural plasticity. In two mouse models of Alzheimer's disease — and in post-mortem samples from human subjects — expression of the epigenetic regulator histone deacetylase 2 (HDAC2) is elevated. Reversing the upregulation of HDAC2 by short-hairpin-RNA-mediated knockdown in mice restores the expression of HDAC2 target genes and abolishes the neurodegeneration-associated memory impairment. Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease1. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge2. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer’s-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer’s disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.

Over the past decade, it has become increasingly obvious that epigenetic mechanisms are an integral part of a multitude of brain functions that range from the development of the nervous system over basic neuronal functions to higher order cognitive processes. At the same time, a substantial body of evidence has surfaced indicating that several neurodevelopmental, neurodegenerative, and neuropsychiatric disorders are in part caused by aberrant epigenetic modifications. Because of their inherent plasticity, such pathological epigenetic modifications are readily amenable to pharmacological interventions and have thus raised justified hopes that the epigenetic machinery provides a powerful new platform for therapeutic approaches against these diseases. In this review, we give a detailed overview of the implication of epigenetic mechanisms in both physiological and pathological brain processes and summarize the state-of-the-art of “epigenetic medicine” where applicable. Despite, or because of, these new and exciting findings, it is becoming apparent that the epigenetic machinery in the brain is highly complex and intertwined, which underscores the need for more refined studies to disentangle brain-region and cell-type specific epigenetic codes in a given environmental condition. Clearly, the brain contains an epigenetic “hotspot” with a unique potential to not only better understand its most complex functions, but also to treat its most vicious diseases.