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Tet3 Deletion in Adult Brain Neurons of Female Mice Results in Anxiety-like Behavior and Cognitive Impairments

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Abstract

TET enzymes (TET1-3) are dioxygenases that oxidize 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and are involved in the DNA demethylation process. In line with the observed 5hmC abundance in the brain, Tet genes are highly transcribed, with Tet3 being the predominant member. We have previously shown that Tet3 conditional deletion in the brain of male mice was associated with anxiety-like behavior and impairment in hippocampal-dependent spatial orientation. In the current study, we addressed the role of Tet3 in female mice and its impact on behavior, using in vivo conditional and inducible deletion from post-mitotic neurons. Our results indicate that conditional and inducible deletion of Tet3 in female mice increases anxiety-like behavior and impairs both spatial orientation and short-term memory. At the molecular level, we identified upregulation of immediate-early genes, particularly Npas4, in both the dorsal and ventral hippocampus and in the prefrontal cortex. This study shows that deletion of Tet3 in female mice differentially affects behavioral dimensions as opposed to Tet3 deletion in males, highlighting the importance of studying both sexes in behavioral studies. Moreover, it contributes to expand the knowledge on the role of epigenetic regulators in brain function and behavioral outcome.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank Wolf Reik and Julian Peat (Babraham Institute, Cambridge, UK) for providing the Tet3 floxed mice and Nuno Sousa (School of Medicine, University of Minho, Portugal) for critical reading of the manuscript.

Funding

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, SFRH/BD/131278/2017 to ELC, SFRH/BD/101298/2014 to SGM, IF/01079/2014 to LP, IF/00047/2012 and CEECIND/00371/2017 to CJM); FCT project grant (PTDC/BIA-BCM/121276/2010) to C.J.M; EpiGeneSys Small Collaborative project to LP; BIAL Foundation Grant 427/14 to LP; and Nature Research Award for Driving Global Impact – 2019 Brain Sciences to LP. It was also co-funded by the Life and Health Sciences Research Institute (ICVS) and by the FEDER (NORTE-01–0145-FEDER-000013), through the Competitiveness Internationalization Operational Program (POCI), and by National funds, through the Foundation for Science and Technology (FCT) – project UIDB/50026/2020 and UIDP/50026/2020. Moreover, this work has been funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI – Portuguese Platform of Bioimaging (PPBI-POCI-01–0145-FEDER-022122; by National funds, through the Foundation or Science and Technology (FCT) – project UIDB/50026/2020 and UIDP/50026/2020).

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Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal

    Cláudia Antunes, Jorge D. Da Silva, Sónia Guerra-Gomes, Nuno D. Alves, Eduardo Loureiro-Campos & Luísa Pinto

  2. ICVS/3B’s – PT Government Associate Laboratory, 4710-057, Braga/Guimarães, Portugal

    Cláudia Antunes, Jorge D. Da Silva, Sónia Guerra-Gomes, Nuno D. Alves, Eduardo Loureiro-Campos & Luísa Pinto

  3. Genetics – Department of Pathology, Faculty of Medicine, University of Porto (FMUP), 4200-319, Porto, Portugal

    C. Joana Marques

  4. i3S – Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, 4200-135, Porto, Portugal

    C. Joana Marques

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  1. Cláudia Antunes
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  2. Jorge D. Da Silva
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  3. Sónia Guerra-Gomes
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  4. Nuno D. Alves
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  5. Eduardo Loureiro-Campos
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  6. Luísa Pinto
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  7. C. Joana Marques
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Contributions

C.A designed the study, performed the experiments, analyzed the data, and wrote the manuscript; J.D.S. performed the statistical analysis; S.G.G. and N.D.A. helped with the behavioral tests and respective analysis; E.L.C. helped with the behavioral tests; L.P. and C.J.M. designed the study and wrote the final manuscript. All authors revised and approved the final manuscript.

Corresponding authors

Correspondence to Luísa Pinto or C. Joana Marques.

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All experiments were conducted in accordance with EU Directive 2010/63/EU and NIH guidelines on animal care and experimentation and were approved by the Portuguese Authorities (DGAV) with the project reference 0421/000/000/2017.

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Antunes, C., Da Silva, J.D., Guerra-Gomes, S. et al. Tet3 Deletion in Adult Brain Neurons of Female Mice Results in Anxiety-like Behavior and Cognitive Impairments. Mol Neurobiol 59, 4892–4901 (2022). https://doi.org/10.1007/s12035-022-02883-7

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