Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function

• Published in: Cell reports (Cambridge) 2022-11, Vol.41 (6), p.111612-111612, Article 111612
• Main Authors: Pratt, Karishma J.B., Shea, Jeremy M., Remesal-Gomez, Laura, Bieri, Gregor, Smith, Lucas K., Couthouis, Julien, Chen, Christopher P., Roy, Irena J., Gontier, Geraldine, Villeda, Saul A.
• Format: Article
• Language: English
• Subjects: 5-Methylcytosine - metabolism; Animals; chromatin; Cognition; Dioxygenases - genetics; DNA Methylation - genetics; DNA-Binding Proteins - metabolism; epigenetics; hippocampus; Hippocampus - metabolism; hydroxymethylation; memory; methylation; Mice; neurons; Neurons - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; TET2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111612

DNA methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here, we report that loss of ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function. In the adult mouse hippocampus, we detected an enrichment of Tet2 in neurons. Viral-mediated neuronal overexpression and RNA interference of Tet2 altered dendritic complexity and synaptic-plasticity-related gene expression in vitro. Overexpression of neuronal Tet2 in adult hippocampus, and loss of Tet2 in adult glutamatergic neurons, resulted in differential hydroxymethylation associated with genes involved in synaptic transmission. Functionally, overexpression of neuronal Tet2 impaired hippocampal-dependent memory, while loss of neuronal Tet2 enhanced memory. Ultimately, these data identify neuronal Tet2 as a molecular target to boost cognitive function. [Display omitted] •Tet2 is enriched in neurons in the adult mouse hippocampus•Tet2 negatively regulates neuronal complexity and synaptic gene expression in vitro•Adult hippocampal neuronal Tet2 alters hydroxymethylation on synaptic gene networks•Neuronal Tet2 negatively regulates memory in the adult hippocampus Pratt et al. identify neuronal Tet2 as a molecular target to boost cognitive function. Tet2-mediated neuronal hydroxymethylation and transcriptional changes negatively regulate adult hippocampal synaptic processes. Increasing neuronal Tet2 impairs hippocampal-dependent memory, while loss of neuronal Tet2 enhances memory.