The maternal X chromosome affects cognition and brain ageing in female mice

Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated^1-4. This renders either the maternal X (X_m) chromosome or the paternal X (X_p) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active^5-7. Parent-of-X origin can modify epigenetics through DNA methylation^8,9 and possibly gene expression; thus, mosaicism could buffer dysregulated processes in ageing and disease. However, whether X skew or its mosaicism alters functions in female individuals is largely unknown. Here we tested whether skew towards an active X_m chromosome influences the brain and body-and then delineated unique features of X_m neurons and X_p neurons. An active X_m chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by X_m-mediated acceleration of biological or epigenetic ageing of the hippocampus, a key centre for learning and memory, in female mice. Several genes were imprinted on the X_m chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of X_m-imprinted genes improved cognition in ageing female mice. Thus, the X_m chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how X_m impairs brain function could lead to an improved understanding of heterogeneity in cognitive health in female individuals and to X-chromosome-derived pathways that protect against cognitive deficits and brain ageing.