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.