RT Journal Article SR Electronic T1 A brain network basis of Fragile X syndrome behavioral penetrance determined by X chromosome inactivation in female mice JF bioRxiv FD Cold Spring Harbor Laboratory SP 458992 DO 10.1101/458992 A1 Eric Szelenyi A1 Danielle Fisenne A1 Joseph E Knox A1 Julie A Harris A1 James A Gornet A1 Ramesh Palaniswamy A1 Yongsoo Kim A1 Kannan Umadevi Venkataraju A1 Pavel Osten YR 2018 UL http://biorxiv.org/content/early/2018/11/02/458992.abstract AB X-chromosome inactivation (XCI) in females is vital for normal brain function and cognition, as many X-linked genetic mutations lead to mental retardation and autism spectrum disorders, such as the fragile X syndrome (FXS). However, the degree by which XCI regulates disease presentation has been poorly investigated. To study this regulation in the mouse, here we quantified the brainwide composition of active-XC cells at single cell resolution using an X-linked MECP2-EGFP allele with known parent-of-origin. We present evidence that whole-brains, including all regions, on average favor maternal XC-active cells by 20%, or 8 million cells. This bias was conserved in heterozygous FXS mutant mice, which also corresponded to disease penetrance in maternal but not paternal FMR1 null mice. To localize the physical source of behavioral penetrance, brain-wide correlational screens successfully mapped mouse performance to cell densities in putative sensorimotor (e.g. sensory hindbrain, thalamus, globus pallidus) and sociability (e.g. visual/entorhinal cortices, bed nucleus stria terminalis, medial preoptic area) behavioral circuits of the open field sensorimotor and 3-chamber sociability assays, respectively. Overall, 50%/50% healthy/mutant cell density ratios in these sub-networks were required for disease presentation in each behavior. These results suggest female X-linked behavioral penetrance of disease is regulated at the distributed level of mutant cell density in behavioral circuits, which is set by XCI that is subject to parent-of-origin effects. This work provides a novel finding behind the broad and varied behavioral phenotypes commonly featured in female patients debilitated by X-linked mental disorders and may offer new entry points for behavioral therapeutics.