Cognitive dysfunction following brain trauma results from sex-specific reactivation of the developmental pruning processes

For decades, researchers have focused on the sequelae of cellular alterations that exist within the perilesional tissues; however, few clinical trials have been successful. Here, we employed a mouse brain injury model that resulted in expansive synaptic damage to regions outside the focal injury.

Our findings demonstrate that synaptic damage results from the prolonged increase in D-serine release from activated microglia and astrocytes, which leads to hyperactivation of perisynaptic NMDARs, tagging of damaged synapses by complement components, and the reactivation of developmental pruning processes. We show that this mechanistic pathway is reversible at several stages within a prolonged and progressive period of synaptic loss.