Significance Depletion of the neural stem cell (NSC) pool is a major driver of age-related regenerative decline in the hippocampus. While increased quiescence is a major contributor to this decline, NSCs can also undergo terminal differentiation into astrocytes, thus restricting the stem cell pool. The mechanisms underlying this fate switch and their relation to age-related regenerative decline have not yet been fully elucidated. In this study, we report an age-related decline in NSC O-GlcNAcylation, coincident with reduced neurogenesis and increased gliogenesis. We identify loss of O-GlcNAcylation at STAT3 T717 in the hippocampus with age, and demonstrate that O-GlcNAcylation of this site is a critical determinant of NSC fate. Our work expands our understanding of how posttranslational modifications influence the aging brain.
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.
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