Inhibition of glial D-serine release rescues synaptic damage after brain injury

Stephen A. Tapanes, Dena Arizanovska, Madelen M. Díaz, Oluwarotimi O. Folorunso, Theresa Harvey, Stephanie E. Brown, Inna Radzishevsky, Liesl N. Close, Jonathan R. Jagid, Joacir Graciolli Cordeiro, Herman Wolosker, Darrick T. Balu, Daniel J. Liebl

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1133-1152
Number of pages20
Issue number6
StateAccepted/In press - 2022
Externally publishedYes


  • D-serine
  • amino acid transporters
  • neuroprotection
  • synaptic damage
  • traumatic brain injury

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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