Astrocytic Control of Glutamate Spillover and Extrasynaptic NMDA Receptor Activation: Implications for Neurodegenerative Disorders
- Vincent Tse1,2
- 1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, Connecticut 06510
- 2Wu Tsai Institute, Yale School of Medicine, New Haven, Connecticut 06510
-
Editor’s Note: These short reviews of recent JNeurosci articles, written exclusively by students or postdoctoral fellows, summarize the important findings of the paper and provide additional insight and commentary. If the authors of the highlighted article have written a response to the Journal Club, the response can be found by viewing the Journal Club at www.jneurosci.org. For more information on the format, review process, and purpose of Journal Club articles, please see http://jneurosci.org/content/jneurosci-journal-club.
-
Author Contributions: V.T. reviewed the literature and wrote the manuscript.
-
Review of Franco and Newman
In several neurodegenerative disorders, glutamate—the primary excitatory neurotransmitter—spills over from the synaptic cleft and drives excessive activation of extrasynaptic NMDA receptors (NMDARs), leading to excitotoxicity (Parsons and Raymond, 2014; Andersen et al., 2021). Therefore, some researchers have attempted to develop treatments for neurodegenerative disorders using general NMDAR blockers to attenuate this excitotoxicity, but without success. Recent studies have suggested a potential reason for this. Specifically, evidence suggests that synaptic NMDARs promote cell survival by activating neuroprotective signaling pathways, whereas extrasynaptic NMDARs promote cell death (Parsons and Raymond, 2014). This means general, nonselective NMDAR blockers are not suitable for directly targeting the excitotoxicity driven by extrasynaptic NMDARs. In other words, this hypothesis suggests new therapies for neurodegenerative disorders would benefit patients if designed to distinguish NMDAR subtypes based on their location and associated biological processes. However, this hypothesis is not universally accepted, and it remains technically challenging to selectively block NMDARs based on their subcellular localization. An alternative, potentially more feasible approach might be to limit glutamate spillover and the subsequent activation of extrasynaptic NMDARs.
A promising cellular target for preventing glutamate spillover and limiting the activation of extrasynaptic NMDARs is astrocytes. These cells take up synaptic glutamate to …
Correspondence should be addressed to Vincent Tse at vincent.tse{at}yale.edu.
