Abstract
Dysregulated immunity has been implicated in the pathogenesis of neurodevelopmental disorders but its contribution to synaptic and behavioral deficits in Rett syndrome (RTT) remains unknown. P2X7 receptors (P2X7Rs) are unique purinergic receptors with pro-inflammatory functions. Here, we report in a MECP2-deficient mouse model of RTT that the border of the cerebral cortex exhibits increased number of inflammatory myeloid cells expressing cell-surface P2X7Rs. Total knockout of P2X7Rs in MECP2 deficient mice decreases the number of inflammatory myeloid cells, restores cortical dendritic spine dynamics, and improves the animals’ neurological function and social behavior. Furthermore, either genetic depletion of P2X7Rs in bone-marrow derived leukocytes or pharmacological block of P2X7Rs primarily outside of the central nervous system parenchyma, recapitulates the beneficial effects of total P2X7R depletion on the social behavior. Together, our results highlight the pathophysiological roles of P2X7Rs in a mouse model of RTT.
Highlights
Dysregulated immunity has been implicated in the pathogenesis of neurodevelopmental disorders but its contribution to synaptic and behavioral deficits in Rett syndrome (RTT) remains unknown
We investigated the pathophysiological roles of P2X7 receptors (P2X7Rs) in a mouse model of RTT with methyl-CpG-binding protein 2 (MECP2) deficiency
We found that Mecp2308/Y mice had an increased number of inflammatory cells expressing P2X7Rs in the border of the cerebral cortex
Summary
Dysregulated immunity has been implicated in the pathogenesis of neurodevelopmental disorders but its contribution to synaptic and behavioral deficits in Rett syndrome (RTT) remains unknown. Rett syndrome has been modeled in rodents with loss of function mutations in MECP2 These mice develop neurological and behavioral phenotypes resembling those observed in RTT patients. Upon activation by ATP, P2X7Rs regulate the production and release of inflammatory mediators, such as IL-1β, TNFα, and PGE2, as well as the oxidation of nitric oxide derivates[17,18] Given their proinflammatory function, P2X7Rs have been proposed as therapeutic targets for various inflammatory and neurological disorders[15,17,19,20,21] as well as for autism-like behavior in mice with maternal immune activation[22,23,24]. Our results underscore the contributions of P2X7Rs and non-microglial myeloid cells to brain dysfunction in RTT
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
