Methamphetamine-associated memory is regulated by a writer and an eraser of permissive histone methylation.

BACKGROUND: Memories associated with drugs of abuse, such as methamphetamine (METH), increase relapse vulnerability to substance use disorder by triggering craving. The nucleus accumbens (NAc) is essential to these drug-associated memories, but underlying mechanisms are poorly understood. Posttranslational chromatin modifications, such as histone methylation, modulate gene transcription; thus, we investigated the role of the associated epigenetic modifiers in METH-associated memory. METHODS: Conditioned place preference was used to assess the epigenetic landscape in the NAc supporting METH-associated memory (n = 79). The impact of histone methylation (H3K4me2/3) on the formation and expression of METH-associated memory was determined by focal, intra-NAc knockdown (KD) of a writer, the methyltransferase mixed-lineage leukemia 1 (Mll1) (n = 26), and an eraser, the histone lysine (K)-specific demethylase 5C (Kdm5c) (n = 38), of H3K4me2/3. RESULTS: A survey of chromatin modifications in the NAc of animals forming a METH-associated memory revealed the global induction of several modifications associated with active transcription. This correlated with a pattern of gene activation, as revealed by microarray analysis, including upregulation of oxytocin receptor (Oxtr) and FBJ osteosarcoma oncogene (Fos), the promoters of which also had increased H3K4me3. KD of Mll1 reduced H3K4me3, Fos and Oxtr levels and disrupted METH-associated memory. KD of Kdm5c resulted in hypermethylation of H3K4 and prevented the expression of METH-associated memory. CONCLUSIONS: The development and expression of METH-associated memory are supported by regulation of H3K4me2/3 levels by MLL1 and KDM5C, respectively, in the NAc. These data indicate that permissive histone methylation, and the associated epigenetic writers and erasers, represent potential targets for the treatment of substance abuse relapse, a psychiatric condition perpetuated by unwanted associative memories.

DNA methylation: a transcriptional mechanism co-opted by the developed mammalian brain?

Forming and maintaining behavioral memories is a complex process that involves, among other requirements, transcriptional regulation and systems communication. Here we review recent studies exploring the role of DNA methylation in these critical processes. Further, we suggest that, perhaps, the adult brain controls and utilizes the mechanism of DNA methylation in non-traditional ways that are waiting to be explored.

The path to epigenetic treatment of memory disorders.

A new line of neuroscience research suggests that epigenetics may be the site of nature and nurture integration by providing the environment with a mechanism to directly influence the read-out of our genome. Epigenetic mechanisms in the brain are a series of post-translational chromatin and DNA modifications driven by external input. Given the critical hub that epigenetics appears to be, neuroscientists have come to suspect its fundamental influence on how our minds change in response to our unique environment and, in turn, how these changes can then impact our future interactions with the environment. The field of learning and memory is becoming particularly interested in understanding the cognitive influence of epigenetics. With the majority of us working with an eye toward therapeutics, the question naturally arises: "Has neuroepigenetics gotten us closer to treating memory disorders and if so, where do we go from here?" This review will begin with a brief exploration of recent advances in our understanding of how epigenetic mechanisms contribute to learning and memory processes that are susceptible to failure. Next the implications for disorders of cognition, such as Alzheimer's disease, will be discussed. Finally, we will use parallels from the field of cancer to speculate on where we should consider heading from here in the pursuit of therapeutics.

The role of imprinted genes in mediating susceptibility to neuropsychiatric disorders.

Imprinted genes, which are thought to comprise <1% of the mammalian genome, are defined by their parent-of-origin specific monoallelic expression arising as a consequence of differential epigenetic marking of alleles in the paternal and maternal germlines. Such genes are highly represented in the brain and placental transcriptomes, and have been shown to exert significant influence on fundamental developmental processes in these organs. Converging evidence from work in man and animal models has shown that imprinted genes can influence a variety of brain and behavioral endophenotypes. In this article, we review the current evidence that imprinted gene dysfunction is associated with vulnerability to several common psychiatric disorders. We also discuss how studying imprinted gene (dys)function may provide mechanistic insights into two important areas in modern psychiatry: first, how environmental factors (especially in utero) interact with genetic liability via epigenetic mechanisms to predispose to later mental illness, and second, the molecular underpinnings of sex-specific vulnerability to psychiatric disorders.