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Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury
Enmanuel J. Perez, … , Joseph T. Coyle, Daniel J. Liebl
Enmanuel J. Perez, … , Joseph T. Coyle, Daniel J. Liebl
Published July 17, 2017
Citation Information: J Clin Invest. 2017;127(8):3114-3125. https://doi.org/10.1172/JCI92300.
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Research Article Neuroscience

Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury

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Abstract

After traumatic brain injury (TBI), glial cells have both beneficial and deleterious roles in injury progression and recovery. However, few studies have examined the influence of reactive astrocytes in the tripartite synapse following TBI. Here, we have demonstrated that hippocampal synaptic damage caused by controlled cortical impact (CCI) injury in mice results in a switch from neuronal to astrocytic d-serine release. Under nonpathological conditions, d-serine functions as a neurotransmitter and coagonist for NMDA receptors and is involved in mediating synaptic plasticity. The phasic release of neuronal d-serine is important in maintaining synaptic function, and deficiencies lead to reductions in synaptic function and plasticity. Following CCI injury, hippocampal neurons downregulated d-serine levels, while astrocytes enhanced production and release of d-serine. We further determined that this switch in the cellular source of d-serine, together with the release of basal levels of glutamate, contributes to synaptic damage and dysfunction. Astrocyte-specific elimination of the astrocytic d-serine–synthesizing enzyme serine racemase after CCI injury improved synaptic plasticity, brain oscillations, and learning behavior. We conclude that the enhanced tonic release of d-serine from astrocytes after TBI underlies much of the synaptic damage associated with brain injury.

Authors

Enmanuel J. Perez, Stephen A. Tapanes, Zachary B. Loris, Darrick T. Balu, Thomas J. Sick, Joseph T. Coyle, Daniel J. Liebl

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Figure 1

Neuronal d-serine is important for synaptic potentiation.

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Neuronal d-serine is important for synaptic potentiation.
d-serine (B) a...
d-serine (B) and SRR (C) immunoreactivity was observed in the CA1 pyramidal cell layer as outlined in a Thy-1–GFP–labeled hippocampus (A). Scale bar: 25 μm. (D) Schematic flow chart of the nSRKO mouse and the aSRKO mouse. (E) I/O curve showed reduced fEPSP amplitude for nSRKO mice at high intensities. Individual traces shown. (F) PPF showed no significant differences between genotypes. (G) LTP was reduced in nSRKO mice as compared with WT and aSRKO mice. Individual traces shown. (H) Histograph of LTP early phase showed reductions in nSRKO mice. (I) Histograph of LTP late phase showed reductions in nSRKO mice. Data represent mean ± SEM. (E–I) n = 5–8/group. (E–G) Two-way RM ANOVA. (H, I) One-way ANOVA. *P < 0.05; **P < 0.01; ***P < 0.001, compared with cSR control mice. #P < 0.05; ###P < 0.001, compared with nSRKO mice.
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