GSE171947
LOSS OF NEURONAL TET2 ENHANCES HIPPOCAMPAL-DEPENDENT COGNITIVE FUNCTION
Chromatin 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. Abrogation of neuronal Tet2 in vitro altered synaptic-plasticity related gene expression. We observed that loss of Tet2 in mature glutamatergic neurons in adult mice resulted in differential hydroxymethylation on genes involved in synaptic transmission in the hippocampus. Correspondingly, RNA sequencing identified changes in both long-term potentiation pathways and immune-related genes linked to synaptic plasticity. Functionally, loss of neuronal Tet2 improved performance on hippocampal-dependent spatial and associative memory tasks. Ultimately, this work identifies neuronal Tet2 as a molecular target to enhance cognitive function. Overall design: hMeDIP sequencing of hippocampal neuronal nuclei isolated from CamKIIaCreERT2;Tet2fl/fl mice vs WT Tet2fl/fl.