Microglial deficiency in the ATRX chromatin remodeler elicits a viral mimicry immune response that impacts neuronal function and behavior

The importance of chromatin-mediated processes in neurodevelopmental and intellectual disability disorders is well recognized. 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 targeted to microglia leads to altered cell morphology, increased chromatin accessibility profiles, and de-repression of endogenous retroelements, triggering viral mimicry. In mice that lack ATRX in microglia, CA1 hippocampal neuron morphology and electrophysiological properties are affected, and the mice display specific behavioral deficits. These findings demonstrate that ATRX is required in microglia to preserve chromatin structure and maintain microglial homeostasis. Disruption of these functions elicits neuroinflammation and may contribute to the pathology of human neurological disorders caused by ATRX mutations.