DNA Methyltransferase 3A Mediates the Sustained Effects of Stress on Synaptic Functions and Behaviors [RRBS]

Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here we found that rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory and aggressive behaviors, were ameliorated by Dnmt3a expression in PFC of stressed animals. Lastly, we found genome-wide DNA methylation changes in PFC of stressed rats are selectively enriched at several pathways, such as axon guidance, Wnt signaling and neurotransmission. These findings have therefore recognized the role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive & emotional processes. Overall design: 4 samples (PFC tissue from one rat/sample) in each group are analyzed