Methamphetamine-Associated Memory Is Regulated by a Writer and an Eraser of Permissive Histone Methylation

Abstract

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 MLL1 (n=26), and an eraser, the histone demethylase 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 Oxtr and Fos, whose promoters 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.

Developmental Perspectives on Oxytocin and Vasopressin

“…*Po0.05, **Po0.01, ***Po0.001. expression levels of Oxtr mRNA (Mamrut et al, 2013;Harony-Nicolas et al, 2014) and is dynamically regulated in the uterine myometrium and mammary tissue at parturition and lactation (Mamrut et al, 2013) and in the brain after drug exposure in adulthood (Aguilar-Valles et al, 2013). There is significant associative evidence that methylation of the human OXTR gene may also contribute to developmental and dynamic regulation of OXTR gene expression (reviewed in Kumsta et al, 2013).…”

Regulation of histone H3K4 methylation in brain development and disease

“…B 369: 20130514 [95]. Fifth, some drugs, including the atypical antipsychotic clozapine and the stimulant metamphetamine, alter H3K4 methylation signatures at specific gene promoters in cerebral cortex and striatum [12,96]. While there is no evidence to date that overall levels of H3K4 methylation are altered in brain tissue of subjects diagnosed with autism or schizophrenia [11,97], changes at specific loci have been reported.…”

Advances in the development of histone lysine demethylase inhibitors

“…KDM5 proteins stimulate cancer cell proliferation, reduce the expression of tumor suppressors, promote the development of drug resistance, the survival of tumorinitiating cells and relapse [35]. KDM5C and REST cooccupy the neuron-restrictive silencing elements and suppress the expression of REST target genes [36]. Loss-of-function of this gene causes mental retardation and affects memory in men and mice, but can also be beneficial in neurodegenerative disease with aberrant REST activity like Huntington's disease [36,37].…”

“…KDM5C and REST cooccupy the neuron-restrictive silencing elements and suppress the expression of REST target genes [36]. Loss-of-function of this gene causes mental retardation and affects memory in men and mice, but can also be beneficial in neurodegenerative disease with aberrant REST activity like Huntington's disease [36,37]. …”