Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons

Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Nature Neuroscience (Impact Factor: 14.98). 03/2010; 13(4):423-30. DOI: 10.1038/nn.2514
Source: PubMed

ABSTRACT Dnmt1 and Dnmt3a are important DNA methyltransferases that are expressed in postmitotic neurons, but their function in the CNS is unclear. We generated conditional mutant mice that lack Dnmt1, Dnmt3a or both exclusively in forebrain excitatory neurons and found that only double knockout (DKO) mice showed abnormal long-term plasticity in the hippocampal CA1 region together with deficits in learning and memory. Although we found no neuronal loss, hippocampal neurons in DKO mice were smaller than in the wild type; furthermore, DKO neurons showed deregulated expression of genes, including the class I MHC genes and Stat1, that are known to contribute to synaptic plasticity. In addition, we observed a significant decrease in DNA methylation in DKO neurons. We conclude that Dnmt1 and Dnmt3a are required for synaptic plasticity, learning and memory through their overlapping roles in maintaining DNA methylation and modulating neuronal gene expression in adult CNS neurons.

Download full-text


Available from: Yu Zhou, Sep 19, 2014
  • Source
    • "Developmental changes of DNMT1 and DNMT3A proteins in mouse hippocampus and neocortex regions We measured the levels of DNMT1 and DNMT3A, enzymes involved in DNA methylation (Biniszkiewicz et al. 2002; Feng et al. 2010), during various stages of brain development . DNMT1 antibody recognized a major band running at 200 kDa (predicted to run at ~183 kDa) as observed in several previous studies (Robertson et al. 2000; Liu et al. 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The significant consequences of ethanol use during pregnancy are neurobehavioral abnormalities involving hippocampal and neocortex malfunctions that cause learning and memory deficits collectively named fetal alcohol spectrum disorder (FASD). However, the molecular mechanisms underlying these abnormalities are still poorly understood and therefore warrant systematic research. Here, we document novel epigenetic abnormalities in the mouse model of FASD. Ethanol treatment of P7 mice, which induces activation of caspase-3, impaired DNA methylation through reduced DNA methyltransferases (DNMT1 and DNMT3A) levels. Inhibition of caspase-3 activity, before ethanol treatment, rescued DNMT1, DNMT3A proteins as well as DNA methylation levels. Blockade of histone methyltransferase (G9a) activity or cannabinoid receptor type-1 (CB1R), prior to ethanol treatment, which respectively inhibits or prevents activation of caspase-3, rescued the DNMT1 and DNMT3A proteins and DNA methylation. No reduction of DNMT1 and DNMT3A proteins and DNA methylation was found in P7 CB1R null mice, which exhibit no ethanol-induced activation of caspase-3. Together, these data demonstrate that ethanol-induced activation of caspase-3 impairs DNA methylation through DNMT1 and DNMT3A in the neonatal mouse brain, and such impairments are absent in CB1R null mice. Epigenetic events mediated by DNA methylation may be one of the essential mechanisms of ethanol teratogenesis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 12/2014; 132(4). DOI:10.1111/jnc.13006 · 4.24 Impact Factor
  • Source
    • "It has been demonstrated that the DNMTs play an important role in synaptic function (Feng et al., 2010). Moreover, we observed that perinatal HFD continued into adulthood decreased the expression of synaptotagmin 4 and synaptophysin , two major molecules involved in vesicle exocytosis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiological observations report an increase in fat consumption associated with low intake of n-3 relative to n-6 polyunsaturated fatty acids (PUFAs) in women of childbearing age. However, the impact of these maternal feeding habits on cognitive function in the offspring is unknown. This study aims to investigate the impact of early exposure to a high-fat diet (HFD) with an unbalanced n-6/n-3 PUFAs ratio on hippocampal function in adult rats. Furthermore, we explored the effects of perinatal HFD combined with exposure to HFD after weaning. Dams were fed a control diet (C, 12% of energy from lipids, n-6/n-3 PUFAs ratio: 5) or HFD (HF, 39% of energy from lipids, n-6/n-3 PUFAs ratio: 39) throughout gestation and lactation. At weaning, offspring were placed either on control (C—C, HF—C) or high-fat (HF—HF) diets. In adulthood, hippocampus-dependent memory was assessed using the water-maze task and potential hippocampal alterations were determined by studying PUFA levels, gene expression, neurogenesis and astrocyte morphology. Perinatal HFD induced long-lasting metabolic alterations and some changes in gene expression in the hippocampus, but had no effect on memory. In contrast, spatial memory was impaired in animals exposed to HFD during the perinatal period and maintained on this diet. HF—HF rats also exhibited low n-3 and high n-6 PUFA levels, decreased neurogenesis and downregulated expression of several plasticity-related genes in the hippocampus. To determine the contribution of the perinatal diet to the memory deficits reported in HF—HF animals, an additional experiment was conducted in which rats were only exposed to HFD starting at weaning (C—HF). Interestingly, memory performance in this group was similar to controls. Overall, our results suggest that perinatal exposure to HFD with an unbalanced n-6/n-3 ratio sensitizes the offspring to the adverse effects of subsequent high-fat intake on hippocampal function.
    Psychoneuroendocrinology 12/2014; 53:82-93. DOI:10.1016/j.psyneuen.2014.12.008 · 5.59 Impact Factor
  • Source
    • "[73] [74] [75] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Early Onset Alzheimer Disease (EOAD) is a rare condition, frequently associated with genetic causes. The dissemination of genetic testing along with biomarker determinations have prompted a wider recognition of EOAD in experienced clinical settings. However, despite the great efforts in establishing the contribution of causative genes to EOAD, atypical disease presentation and clinical features still makes its diagnosis and treatment a challenge for the clinicians. This review aims to provide an extensive evaluation of literature data on EOAD, in order to improve understanding and knowledge of EOAD, underscore its significant impact on patients and their caregivers and influence public policies. This would be crucial to define the urgency of evidence-based treatment approaches.
    Current Alzheimer Research 11/2014; 11(10). DOI:10.2174/1567205011666141107151606 · 3.80 Impact Factor
Show more

Similar Publications