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Abstract

Adult neurogenesis enables the life-long addition of functional neurons
to the hippocampus and is regulated by both cell-intrinsic molecular
programs and behavioral activity. De novo DNA methylation is crucial for
embryonic brain development, but its role during adult hippocampal
neurogenesis has remained unknown. Here, we show that de novo DNA
methylation is critical for maturation and functional integration of
adult-born neurons in the mouse hippocampus. Bisulfite sequencing
revealed that de novo DNA methyltransferases target neuronal enhancers
and gene bodies during adult hippocampal neural stem cell
differentiation, to establish neuronal methylomes and facilitate
transcriptional up-regulation of neuronal genes. Inducible deletion of
both de novo DNA methyltransferases Dnmt3a and Dnmt3b in adult neural
stem cells did not affect proliferation or fate specification, but
specifically impaired dendritic outgrowth and synaptogenesis of newborn
neurons, thereby hampering their functional maturation. Consequently,
abolishing de novo DNA methylation modulated activation patterns in the
hippocampal circuitry and caused specific deficits in
hippocampus-dependent learning and memory. Our results demonstrate that
proper establishment of neuronal methylomes during adult neurogenesis is
fundamental for hippocampal function.