Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens

Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.
Nature Neuroscience (Impact Factor: 16.1). 09/2010; 13(9):1137-43. DOI: 10.1038/nn.2619
Source: PubMed


Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.

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    • "Changes in DNMT gene expression as well as DNA methylation have also been shown to take place in psychiatric diseases such as schizophrenia (Tremolizzo et al., 2002; Veldic et al., 2005). Observations have also been made that involve other epigenetic mechanisms, such as histone acetylation that has been shown to be implicated in numerous brain activities such as memory formation (Fischer et al., 2007; LaPlant et al., 2010); and neurodegenerative diseases such as Huntington's disease (Butler and Bates, 2006). Thus, strong evidence supports a critical role for epigenetic regulation of CNS activity in adult animals. "
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    ABSTRACT: Neuropathic pain is associated with hyperexcitability and intrinsic firing of dorsal root ganglia (DRG) neurons. These phenotypical changes can be long lasting, potentially spanning the entire life of animal models, and depend on altered expression of numerous proteins, including many ion channels. Yet, how DRGs maintain long-term changes in protein expression in neuropathic conditions remains unclear. DNA methylation is a well-known mechanism of epigenetic control of gene expression and is achieved by the action of three enzymes: DNA methyltransferase (DNMT) 1, 3a, and 3b, which have been studied primarily during development. We first performed immunohistochemical analysis to assess whether these enzymes are expressed in adult rat DRGs (L4–5) and found that DNMT1 is expressed in both glia and neurons, DNMT3a is preferentially expressed in glia and DNMT3b is preferentially expressed in neurons. A rat model of neuropathic pain was then used to determine whether nerve injury may induce epigenetic changes in DRGs at multiple time points after pain onset. Real-time RT PCR analysis revealed robust and time-dependent changes in DNMT transcript expression in ipsilateral DRGs from spared nerve injury (SNI) but not sham rats. Interestingly, DNMT3b transcript showed a robust upregulation that appeared already 1 week after surgery and persisted at 4 weeks (our endpoint); in contrast, DNMT1 and DNMT3a transcripts showed only moderate upregulation that was transient and did not appear until the second week. We suggest that DNMT regulation in adult DRGs may be a contributor to the pain phenotype and merits further study.
    Full-text · Article · Aug 2014 · Frontiers in Cellular Neuroscience
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    • "Further study revealed that these changes were linked to changes in HDAC activity, and HDAC5 was found to mimic the properties of antidepressants in protecting against the behavioral effects of chronic stress or cocaine [91]. DNA methylation in the accumbens was also linked to chronic social defeat, as DNMT3a expression increased in defeated animals, and the increase was found to be correlated with plastic changes in dendritic spines [92]. Much like humans, a substantial fraction of mice show resilience to defeat stress; in these animals, DNA methylation of the CRH promoter in the PVN was maintained while in defeated animals it was demethylated [93]. "
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    Full-text · Chapter · Jul 2014
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    • "To understand the behavioral importance of MBII-52 downregulation in NAc after repeated cocaine exposure or cocaine-induced CPP, mice were received intra-NAc injections of lentiviruses expressing MBII-52 (LV-MBII-52) to temporally and specifically overexpress MBII-52 in the NAc (Fig. 3A), and then evaluated whether such genetic manipulation could block cocaine-induced CPP, which provides an indirect measure of cocaine reward [18], [19]. Importantly, MBII-52 overexpression in this brain region markedly attenuated the preference for cocaine in comparison to that seen in animals expressing GFP (Fig. 3B). "
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    ABSTRACT: Cocaine dependence involves in the brain's reward circuit as well as nucleus accumbens (NAc), a key region of the mesolimbic dopamine pathway. Many studies have documented altered expression of genes and identified transcription factor networks and epigenetic processes that are fundamental to cocaine addiction. However, all these investigations have focused on mRNA and/or miRNA, which may not reflect the involvement of small nucleolar RNAs (snoRNAs), which has been implied in a broad range of biological processes and complex diseases including brain development and neuropathologocal process. To further address the role of snoRNA in cocaine addiction, we show that repeated exposure and conditioned place preference (CPP) training to cocaine negatively regulates the expression of MBII-52 mRNA level, which is a brain-specific C/D box snoRNA, but not influences the serotonin receptor 2C (5HT2CR) mRNA level in NAc. Furthemore, we show, developing lentiviral vector (LV)-expressing MBII-52 and LV-5HT2CR for stable and regulatable MBII-52 and LV-5HT2CR expression. LV-MBII-52 and LV-5HT2CR expression in NAc attenuate cocaine induced CPP and locomotor activity. Taken together, these findings show that MBII-52 and 5HT2CR exert an inhibitory influence on the behavioral responses to cocaine exposure.
    Full-text · Article · Jun 2014 · PLoS ONE
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