Academic Commons

Articles

A Single Day of 5-Azacytidine Exposure during Development Induces Neurodegeneration in Neonatal Mice and Neurobehavioral Deficits in Adult Mice

Subbanna, Shivakumar; Nagre, Nagaraja N.; Shivakumar, Madhu; Basavarajappa, Balapal S.

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.

Files

  • thumnail for 2016-Physiology & Behavior.pdf 2016-Physiology & Behavior.pdf application/pdf 2.43 MB Download File

Also Published In

Title
Physiology & Behavior
DOI
https://doi.org/10.1016/j.physbeh.2016.08.036

More About This Work

Academic Units
Psychiatry
Published Here
March 3, 2018
Academic Commons provides global access to research and scholarship produced at Columbia University, Barnard College, Teachers College, Union Theological Seminary and Jewish Theological Seminary. Academic Commons is managed by the Columbia University Libraries.