Shafiq, S.; Ghahramani, A.; Mansour, K.; Pena-Ortiz, M.; Sunstrum, J. K.; Jiang, Y.; Rowland, M. E.; Inoue, W.; Berube, N. G.

The importance of chromatin-mediated processes in neurodevelopmental and intellectual disability disorders is well recognised. However, how chromatin dysregulation in glial cells impacts cognitive abilities is less well understood. Here, we demonstrate that targeted loss of the ATRX chromatin remodeler in microglia alters chromatin accessibility profiles, leading to the de-repression of endogenous retroelements, triggering viral mimicry. Functionally, we find that ATRX microglial deficiency alters the electrophysiological properties of hippocampal neurons and causes deficits in object recognition and spatial memory. Overall, these findings demonstrate that ATRX is required in microglia to preserve chromatin structure and maintain microglial homeostasis. Disruption of these functions elicit neuroinflammation and cognitive deficits and potentially contribute to the pathology of human neurological disorders caused by ATRX mutations.