Tet3 Ablation in Adult Brain Neurons Increases Anxiety-like Behavior and Regulates Cognitive Function in Mice

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2020 Feb 28

PMID 32103150

Citations 32

Authors

Claudia Antunes

Jorge D Da Silva

Sonia Guerra-Gomes

Nuno D Alves

Fabio Ferreira

Eduardo Loureiro-Campos

Miguel R Branco

Nuno Sousa

Wolf Reik

Luisa Pinto

C Joana Marques

Affiliations

Soon will be listed here.

Abstract

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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