LAUSR

HIGHLIGHTSMeCP2 in the adult hippocampus is required for long‐term memory formation.MeCP2 maintains the chromatin features of mature CA1 neurons.MeCP2 preserves the genomic responsiveness to hippocampus‐dependent learning. ABSTRACT MeCP2 is required both during postnatal neurodevelopment and throughout the adult life for brain function. Although it is well accepted that MeCP2 in the maturing nervous system is critical for establishing normal development, the functions of MeCP2 during adulthood are poorly understood. Particularly, the requirement of hippocampal MeCP2 for cognitive abilities in the adult is not studied. To characterize the role of MeCP2 in adult neuronal function and cognition, we used a temporal and region‐specific disruption of MeCP2 expression in the hippocampus of adult male mice. We found that MeCP2 is required for long‐term memory formation and that it controls the learning‐induced transcriptional response of hippocampal neurons required for memory consolidation. Furthermore, we uncovered MeCP2 functions in the adult hippocampus that may underlie cognitive integrity. We showed that MeCP2 maintains the developmentally established chromatin configuration and epigenetic landscape of CA1 neurons throughout the adulthood, and that it regulates the expression of neuronal and immune‐related genes in the adult hippocampus. Overall, our findings identify MeCP2 as a maintenance factor in the adult hippocampus that preserves signal responsiveness of the genome and allows for integrity of cognitive functions. This study provides new insight into how MeCP2 maintains adult brain functions, but also into the mechanisms underlying the cognitive impairments observed in RTT patients and highlights the understudied role of DNA methylation interpretation in adult cognitive processes.