Tet1 overexpression leads to anxiety‐like behavior and enhanced fear memories <i>via</i> the activation of calcium‐dependent cascade through Egr1 expression in mice

Abstract

Ten-eleven translocation methylcytosine dioxygenase 1 (<i>Tet1</i>) initiates DNA demethylation by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) at CpG-rich regions of genes, which have key roles in adult neurogenesis and memory. In addition, the overexpression of Tet1 with 5-hmC alteration in patients with psychosis has also been reported, for instance in schizophrenia and bipolar disorders. The mechanism underlying Tet1 overexpression in the brain; however, is still elusive. In the present study, we found that Tet1-transgenic (Tet1-TG) mice displayed abnormal behaviors involving elevated anxiety and enhanced fear memories. We confirmed that Tet1 overexpression affected adult neurogenesis with oligodendrocyte differentiation in the hippocampal dentate gyrus of Tet1-TG mice. In addition, Tet1 overexpression induced the elevated expression of immediate early genes, such as <i>Egr1</i>, <i>c-fos</i>, <i>Arc</i>, and <i>Bdnf</i>, followed by the activation of intracellular calcium signals (<i>i.e.</i>, CamKII, ERK, and CREB) in prefrontal and hippocampal neurons. The expression of GABA receptor subunits (<i>Gabra2</i> and <i>Gabra4</i>) fluctuated in the prefrontal cortex and hippocampus. We evaluated the effects of Tet1 overexpression on intracellular calcium-dependent cascades by activating the <i>Egr1</i> promoter <i>in vitro</i> Tet1 enhanced Egr1 expression, which may have led to alterations in <i>Gabra2</i> and <i>Gabra4</i> expression in neurons. Taken together, we suggest that the Tet1 overexpression in our Tet1-TG mice can be applied as an effective model for studying various stress-related diseases that show hyperactivation of intracellular calcium-dependent cascades in the brain.-Kwon, W., Kim, H.-S., Jeong, J., Sung, Y., Choi, M., Park, S., Lee, J., Jang, S., Kim, S. H., Lee, S., Kim, M. O., Ryoo, Z. Y. Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories <i>via</i> the activation of calcium-dependent cascade through Egr1 expression in mice.