Abstract
Traumatic brain injury (TBI) is a major health concern worldwide affecting up to 69 million people annually. One of the major components underlying TBI pathology is long lasting synaptic damage. Despite the severity of consequences, little is understood about persistent synaptic damage in the injured brain. D-serine is a co-agonist for NMDARs. D-serine is synthesized from L-serine by the enzyme serine racemase (SRR) and has previously been shown to contribute to synaptic dysfunction after injury. We examined the expression and function of D-serine, SRR, and D-serine transporters in a murine model of controlled cortical impact (CCI) injury. We identified a switch in SRR expression from neurons to microglia and astrocytes after injury that contributed to synaptic loss and deficits in learning and memory. Furthermore, we examined the role of glial D-serine transporters in the injured brain and found they contribute to synaptic loss and cognitive deficits, where inhibition of glial D-serine transport contributed to attenuation of synaptic damage. In short, our findings implicate glial D-serine in synaptic pathology and demonstrate that preventing glial D-serine synthesis or release abolishes injury-induced damage and cognitive deficits. This uncovers a major pathological pathway that may present a significant therapeutic target to protect synaptic function following TBI.