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

Now we just need someone to put this together into a protocol and distribute it effectively to all stroke hospitals(meaning the stroke hospital implements the protocol). That will never occur, we have NO leadership that will ensure it gets done.

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

Stephen A. Tapanes1| Dena Arizanovska1| Madelen M. Díaz1|Oluwarotimi O. Folorunso2,3| Theresa Harvey3| Stephanie E. Brown3|Inna Radzishevsky4| Liesl N. Close1| Jonathan R. Jagid1|Joacir Graciolli Cordeiro1| Herman Wolosker4| Darrick T. Balu2,3| Daniel J. Liebl1

1The Miami Project to Cure Paralysis,Department of Neurological Surgery,University of Miami Miller School of Medicine,Miami, Florida, USA2Department of Psychiatry, Harvard MedicalSchool, Boston, Massachusetts, USA3Translational Psychiatry Laboratory, McLeanHospital, Belmont, Massachusetts, USA4Department of Biochemistry, RappaportFaculty of Medicine, Technion-Israel Instituteof Technology, Haifa, IsraelCorrespondenceDaniel J. Liebl, The Miami Project to CureParalysis, The University of Miami, 1095 NW14th Terrace, R-48, Miami, FL 33136, USA.

Abstract 

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.