Tet1 in nucleus accumbens regulates stress responses

Depression is a leading cause of disease burden, yet current therapies fully treat <50% of affected individuals. Increasing evidence implicates epigenetic mechanisms in depression and antidepressant action. Here, we examined a possible role for the newly identified methylcytosine oxidase, ten eleven translocation protein 1 (TET1), in depression-related behavioral abnormalities. We show that chronic social defeat stress, an ethologically validated mouse model of depression, decreased Tet1 expression in nucleus accumbens (NAc), a key brain reward region, in stress susceptible mice only. Surprisingly, selective knockout of Tet1 in NAc neurons of adult mice produced antidepressant-like effects in several behavioral assays. To identify Tet1 targets that mediate these actions, we performed RNAseq on NAc after Tet1 knockout and found that immune-related genes are the most highly regulated. Interestingly, many of these genes are also upregulated in NAc of resilient mice after chronic social defeat stress. Together, these findings link Tet1 to stress responses and identify novel targets for future antidepressant drug discovery efforts. Overall design: mRNA was collected from TET1 loxp/loxp mouse nucleus accumbens 4 weeks after AAV-Cre injection with AAV-GFP as control. RNAseq was then performed.

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Feng J, Pena CJ, Purushothaman I, Engmann O, Walker D, Brown AN, Issler O, Doyle M, Harrigan E, Mouzon E, Vialou V, Shen L, Dawlaty MM, Jaenisch R, Nestler EJ