TET3 is a member of the ten-eleven translocation (TET) family of enzymes which oxidize 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Tet3 is highly expressed in the brain, where 5hmC levels are most abundant. In adult mice, we observed that TET3 is present in mature neurons and oligodendrocytes but is absent in astrocytes. To investigate the function of TET3 in adult postmitotic neurons, we crossed Tet3 floxed mice with a neuronal Cre-expressing mouse line, Camk2a-CreERT2, obtaining a Tet3 conditional KO (cKO) mouse line. Ablation of Tet3 in adult mature neurons resulted in increased anxiety-like behavior with concomitant hypercorticalism, and impaired hippocampal-dependent spatial orientation. Transcriptome and gene-specific expression analysis of the hippocampus showed dysregulation of genes involved in glucocorticoid signaling pathway (HPA axis) in the ventral hippocampus, whereas upregulation of immediate early genes was observed in both dorsal and ventral hippocampal areas. In addition, Tet3 cKO mice exhibit increased dendritic spine maturation in the ventral CA1 hippocampal subregion. Based on these observations, we suggest that TET3 is involved in molecular alterations that govern hippocampal-dependent functions. These results reveal a critical role for epigenetic modifications in modulating brain functions, opening new insights into the molecular basis of neurological disorders.
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We thank Julian Peat and Christel Krueger (Babraham Institute, UK) for help with the Tet3 floxed mice, João Sobral (Genomics Unit, IGC, Portugal) for RNA-Seq analysis, and Daniel Neves and Daniel Sobral (Bioinformatics Unit, IGC, Portugal) for Bioinformtaic analysis. This work was supported by National Funds through Foundation for Science and Technology (FCT) fellowships (PD/BD/106049/2015 to CA, PD/BD/128074/2016 to JDS, IF/01079/2014 to LP, SFRH/BD/101298/2014 to SGG, SFRH/BD/131278/2017 to ELC, and IF/00047/2012 and CEECIND/00371/2017 to CJM); FCT project grant (PTDC/BIA-BCM/121276/2010) to CJM; EpiGeneSys Small Collaborative project to LP and MRB; BIAL Foundation Grant 427/14 to LP; Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER; NORTE-01-0145-FEDER-000013); FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and National Funds, through the FCT (POCI-01-0145-FEDER-007038).
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Antunes, C., Da Silva, J.D., Guerra-Gomes, S. et al. Tet3 ablation in adult brain neurons increases anxiety-like behavior and regulates cognitive function in mice. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0695-7