Dnmt3a in the Medial Prefrontal Cortex Regulates Anxiety-Like Behavior in Adult Mice

Dnmt3a1 viral overexpression in mouse dorsal mPFC rescued CSDS-induced anxiety.

“Dnmt3a1 viral overexpression in mouse dorsal mPFC, which regulates fear, anxiety, risk taking, and decision-making, rescued CSDS-induced anxiety (Chocyk et al., 2013; Elliott et al., 2016).”

NR3C1 encodes the glucocorticoid receptor, which binds cortisol to regulate HPA axis response.

“NR3C1, the gene that encodes for the GR, which binds to the stress hormone cortisol to regulate HPA axis response”

Dnmt3a may exert anxiolytic effects when expressed through a pathway involving the negative glucocorticoid response element upstream of Dnmt3a1 and NR3C1.

“suggesting a possible pathway through which Dnmt3a may exert anxiolytic effects when expressed. (Elliott et al., 2016).”

Knockdown of Dnmt3a in the mPFC of rats resulted in an anxiety-like phenotype, contrary to the reduced anxiety behaviors observed following decreased Dnmt3a expression in the mouse hippocampus.

“Last, knockdown of Dnmt3a in the mPFC of rats resulted in an anxiety-like phenotype in the study by Elliott et al. (2016), contrary to the reduced anxiety behaviors observed following a decrease in Dnmt3a expression in the mouse hippocampus in the research of Ishii et al. (2014).”

Dnmt3a1, a splice variant of Dnmt3a, was significantly reduced in CSDS mice, with no relevant changes in Dnmt3a2.

“More specifically, Dnmt3a1, a splice variant of Dnmt3a, was significantly reduced in CSDS mice, with no relevant changes in Dnmt3a2 (Elliott et al., 2016).”

Viral knockdown of Dnmt3a induced the same anxiety-like phenotype previously observed in CSDS mice as measured by the elevated plus maze test.

“Viral knockdown of Dnmt3a induced the same anxiety-like phenotype previously observed in CSDS mice as measured by the elevated plus maze (EPM) test, while Dnmt3a1 viral overexpression in mouse dorsal mPFC, which regulates fear, anxiety, risk taking, and decision-making, rescued CSDS-induced anxiety (Chocyk et al., 2013; Elliott et al., 2016).”

A negative glucocorticoid response element sequence upstream of the Dnmt3a1 TSS specifically binds to NR3C1.

“Most interestingly, the researchers found a negative glucocorticoid response element sequence upstream of Dnmt3a1 TSS, which specifically binds to NR3C1, the gene that encodes for the GR, which binds to the stress hormone cortisol to regulate HPA axis response, suggesting a possible pathway through which Dnmt3a may exert anxiolytic effects when expressed. (Elliott et al., 2016).”

In C57BL/6J mice exposed to aggressive CD1 mice to induce chronic social defeat stress, Dnmt3a was selectively downregulated in the medial prefrontal cortex.

“In another study, C57BL/6J mice exposed to aggressive CD1 mice to induce chronic social defeat stress (CSDS), displayed selective downregulation of Dnmt3a in their medial prefrontal cortex (mPFC; Elliott et al., 2016).”

The Dnmt3a downregulation in CSDS mice correlated with a significant reduction in global DNA methylation of the mPFC.

“This correlated with a significant reduction in global DNA methylation of the mPFC, contrary to the increased methylation observed in human blood samples.”