A single day of 5-azacytidine exposure during development induces neurodegeneration in neonatal mice and neurobehavioral deficits in adult mice.
The present study was undertaken to evaluate the immediate and long-term effects of a single-day exposure to 5-Azacytidine (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 (ERK1/2) 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.
Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
Shivakumar
S
Subbanna
Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
Nagaraja N
NN
Nagre
Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
Madhu
M
Shivakumar
Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA; New York State Psychiatric Institute, New York, NY 10032, USA; Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: Basavaraj.Balapal@nki.rfmh.org.
Balapal S
BS
Basavarajappa
D000818:Animals; D000831:Animals, Newborn; D001374:Azacitidine / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced*; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012919:Social Behavior
D004791:Enzyme Inhibitors; D043884:Receptor, Cannabinoid, CB1; D010751:Phosphopyruvate Hydratase; D001374:Azacitidine
DNA methylation; Developing brain; Epigenetics; Methyltransferase; Neuronal loss; Synaptic plasticity