Synaptic damage is one of the most prevalent pathophysiological responses to traumatic CNS injury and underlies much of the associated cognitive dysfunction; however, it is poorly understood. The D‐amino acid, D‐serine, serves as the primary co‐agonist at synaptic NMDA receptors (NDMARs) and is a critical mediator of NMDAR‐dependent transmission and synaptic plasticity. In physiological conditions, D‐serine is produced and released by neurons from the enzymatic conversion of L‐serine by serine racemase (SRR). However, under inflammatory conditions, glial cells become a major source of D‐serine. Here, we report that D‐serine synthesized by reactive glia plays a critical role in synaptic damage after traumatic brain injury (TBI) and identify the therapeutic potential of inhibiting glial D‐serine release though the transporter Slc1a4 (ASCT1). Furthermore, using cell‐specific genetic strategies and pharmacology, we demonstrate that TBI‐induced synaptic damage and memory impairment requires D‐serine synthesis and release from both reactive astrocytes and microglia. Analysis of the murine cortex and acutely resected human TBI brain also show increased SRR and Slc1a4 levels. Together, these findings support a novel role for glial D‐serine in acute pathological dysfunction following brain trauma, whereby these reactive cells provide the excess co‐agonist levels necessary to initiate NMDAR‐mediated synaptic damage.
Syndecan (Sdc) is a transmembrane heparan sulfate proteoglycan that plays a crucial role in axon guidance and synapse formation during CNS development in Drosophila melanogaster. To further examine the effect of syndecan on CNS function, Sdc23 mutant D. melanogaster larvae were used to examine odor preference and the capacity for learning and memory. A series of olfaction assays in both wild type and mutant larvae were performed to characterize naive odor responses before adding a training period to identify the capacity for associative learning. These results showed that Sdc23 larvae prefer odors that wild type larvae do not respond to, suggesting a difference in odor receptor pathways and wiring. In addition, associative learning has been documented in wild type larvae, yet no evidence of associative learning in Sdc23 larvae was found, suggesting that the syndecan also plays a role in learning and memory in D. melanogaster larvae.
KEYWORDS: Syndecan; Proteoglycans; Neurodevelopment; Axon Guidance; Olfaction; Attraction Index; Associative Learning; Drosophila
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