Remodeling of synaptome architecture following traumatic brain injury

In the brain, excitatory synapse diversity is organized into a brainwide synaptome architecture. Traumatic brain injury is associated with synapse loss, but its impact upon synaptome architecture is unknown. Using synaptome mapping across 222 brain regions in mice, we show that lateral fluid percussion injury induces a progressive and distributed reorganization of excitatory synapse populations over 28 days. Although whole-brain synapse number is preserved, specific molecular types and subtypes of synapses exhibit region- and time-dependent vulnerability. At 7 days after injury, synapse types with rapid turnover of the postsynaptic scaffold protein PSD95 are preferentially reduced. However, by 28 days, they have increased, whereas those synapses with slow turnover are reduced. Microglial activation correlated with this synaptome remodeling in a temporally structured manner. These findings reveal a two-phase, proteostasis-linked reprogramming of synaptome architecture, suggesting that large-scale rebalancing of molecularly distinct synapse populations is a general mechanism underlying injury-induced brain plasticity.