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

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.

Information-Rich, Dual-Function 13C/2H-Isotopic Crosstalk NMR Assay for Human Serine Racemase (hSR) Provides a PLP-Enzyme “Partitioning Fingerprint” and Reveals Disparate Chemotypes for hSR Inhibition

“…More recently, the Coyle lab provided compelling evidence that neurotoxic astrocytes associated with Alzheimer’s disease overexpress SR, consistent with earlier observations of Mori and Panizzutti . These findings align with emerging reports of the role of hSR in neuronal disorders including amyotrophic lateral sclerosis (ALS), neuropathic pain, chronic social defeat stress, post-traumatic stress (PTSD) syndrome, and traumatic brain injury . As hSR is the sole source of d -Ser in human neurobiology, there is clearly a need for better tools to study this enzyme and for inhibitors/activators to modulate its activity as tools for chemical biology.…”

“…Whereas d -amino acids used to be considered the domain of bacterial biology, we now know that d -Ser is a critical neuronal signaling molecule in human biology, serving as the principal coagonist of the NMDA receptor (NMDAR). Normal d -Ser signaling at the NMDAR is essential for long-term potentiation (LTP) associated with learning and memory. , On the other hand, hSR hyperfunction is associated with Alzheimer’s disease, ALS, and neuronal infarction pursuant to ischemic stroke, whereas hSR hypofunction correlates with schizophrenia . Moreover, recent work indicates that the second hSR function, namely, β-elimination of l -Ser to pyruvate, and thence acetyl-CoA, is a hallmark of colorectal cancer, leading to elevated metabolism and acetylation of histone H3 …”

“…20 These findings align with emerging reports of the role of hSR in neuronal disorders including amyotrophic lateral sclerosis (ALS), 21 neuropathic pain, 22 chronic social defeat stress, 23 post-traumatic stress (PTSD) syndrome, 24 and traumatic brain injury. 25 As hSR is the sole source of D-Ser in human neurobiology, there is clearly a need for better tools to study this enzyme and for inhibitors/ activators to modulate its activity as tools for chemical biology. Interestingly, hSR catalyzes the β-elimination of L-Ser to pyruvate even more effectively than it racemizes L-Ser to D-Ser (k cat /K m (β-elim):k cat /K m (rac) ∼ 4:1).…”

Calcium signaling in astrocytes and gliotransmitter release

“…ATP can be released via hemichannels, exocytosis, anion channels, and lysosomes (Bezzi and Volterra, 2001;Fujii et al, 2017;Xiong et al, 2018). Lastly, D-serine has been shown to be released via exocytosis, BEST-1, and hemichannels (Wolosker et al, 1999;Martineau et al, 2013;Sild and Van Horn, 2013;Herman, 2018;Koh et al, 2022;Linsambarth et al, 2022;Park et al, 2022;Tapanes et al, 2022). Created with BioRender.com.…”

Addendum to “Emerging evidence for astrocyte dysfunction in schizophrenia”

“…Moreover, the molecular and functional signatures of one single astrocyte may vary with region‐or even synapse specific features and from one to another cell depending on the environmental conditions. For example, inflammatory factors induce the a huge expression of serine racemase in astrocytes (Balu et al, 2019; Perez et al, 2017; Tapanes et al, 2022). Interestingly, L‐serine and its precursors are not abundant in neurons but primarily found in glial cells, which suggests that, although neurons have high levels of serine racemase, they require an external source of L‐serine.…”