Journal
PHYSIOLOGY & BEHAVIOR
Volume 167, Issue -, Pages 16-27Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.physbeh.2016.08.036
Keywords
Developing brain; Epigenetics; Methyltansferase; Neuronal loss; Synaptic plasticity; DNA methylation
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Funding
- National Institute of Alcohol and Alcoholism [RO1-AA019443]
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The present study was undertaken to evaluate the immediate and long-term effects of a single-day exposure to 5Azacytidine (5-AzaC), a DNA methyltransferase inhibitor, on neurobehavioral abnormalities in mice. Our findings suggest that the 5-AzaC treatment significantly inhibited DNA methylation, impaired extracellular signal-regulated kinase (ERKI/2) activation and reduced expression of the activity-regulated cytoskeleton-associated protein (Arc). These events lead to the activation of caspase-3 (a marker for neurodegeneration) in several brain regions, including the hippocampus and cortex, two brain areas that are essential for memory formation and memory storage, respectively. 5-AzaC treatment of P7 mice induced significant deficits in spatial memory, social recognition, and object memory in adult mice and deficits in long-term potentiation (LTP) in adult hippocampal slices. Together, these data demonstrate that the inhibition of DNA methylation by 5-AzaC treatment in P7 mice causes neurodegeneration and impairs ERK1/2 activation and Arc protein expression in neonatal mice and induces behavioral abnormalities in adult mice. DNA methylation-mediated mechanisms appear to be necessary for the proper maturation of synaptic circuits during development, and disruption of this process by 5-AzaC could lead to abnormal cognitive function. Published by Elsevier Inc.
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