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K⁺ efflux through postsynaptic NMDA receptors suppresses local astrocytic glutamate uptake.

ABSTRACT: Glutamatergic transmission prompts K⁺ efflux through postsynaptic NMDA receptors. The ensuing hotspot of extracellular K⁺ elevation depolarizes presynaptic terminal, boosting glutamate release, but whether this also affects glutamate uptake in local astroglia has remained an intriguing question. Here, we find that the pharmacological blockade, or conditional knockout, of postsynaptic NMDA receptors suppresses use-dependent increase in the amplitude and duration of the astrocytic glutamate transporter current (I_GluT ), whereas blocking astrocytic K⁺ channels prevents the duration increase only. Glutamate spot-uncaging reveals that astrocyte depolarization, rather than extracellular K⁺ rises per se, is required to reduce the amplitude and duration of I_GluT . Biophysical simulations confirm that local transient elevations of extracellular K⁺ can inhibit local glutamate uptake in fine astrocytic processes. Optical glutamate sensor imaging and a two-pathway test relate postsynaptic K⁺ efflux to enhanced extrasynaptic glutamate signaling. Thus, repetitive glutamatergic transmission triggers a feedback loop in which postsynaptic K⁺ efflux can transiently facilitate presynaptic release while reducing local glutamate uptake.

SUBMITTER: Tyurikova O

PROVIDER: S-EPMC9132042 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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K+ efflux through postsynaptic NMDA receptors suppresses local astrocytic glutamate uptake.

Tyurikova Olga O Shih Pei-Yu PY Dembitskaya Yulia Y Savtchenko Leonid P LP McHugh Thomas J TJ Rusakov Dmitri A DA Semyanov Alexey A

Glia 20220127 5

Glutamatergic transmission prompts K+ efflux through postsynaptic NMDA receptors. The ensuing hotspot of extracellular K+ elevation depolarizes presynaptic terminal, boosting glutamate release, but whether this also affects glutamate uptake in local astroglia has remained an intriguing question. Here, we find that the pharmacological blockade, or conditional knockout, of postsynaptic NMDA receptors suppresses use-dependent increase in the amplitude and duration of the astro ...[more]

PMID: 35084774

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Project description:Activation of several subtypes of glutamate receptors contributes to changes in postsynaptic calcium concentration at hippocampal synapses, resulting in various types of changes in synaptic strength. Thus, while activation of NMDA receptors has been shown to be critical for long-term potentiation (LTP) and long term depression (LTD) of synaptic transmission, activation of metabotropic glutamate receptors (mGluRs) has been linked to either LTP or LTD. While it is generally admitted that dynamic changes in postsynaptic calcium concentration represent the critical elements to determine the direction and amplitude of the changes in synaptic strength, it has been difficult to quantitatively estimate the relative contribution of the different types of glutamate receptors to these changes under different experimental conditions. Here we present a detailed model of a postsynaptic glutamatergic synapse that incorporates ionotropic and mGluR type I receptors, and we use this model to determine the role of the different receptors to the dynamics of postsynaptic calcium with different patterns of presynaptic activation. Our modeling framework includes glutamate vesicular release and diffusion in the cleft and a glutamate transporter that modulates extracellular glutamate concentration. Our results indicate that the contribution of mGluRs to changes in postsynaptic calcium concentration is minimal under basal stimulation conditions and becomes apparent only at high frequency of stimulation. Furthermore, the location of mGluRs in the postsynaptic membrane is also a critical factor, as activation of distant receptors contributes significantly less to calcium dynamics than more centrally located ones. These results confirm the important role of glutamate transporters and of the localization of mGluRs in postsynaptic sites in their signaling properties, and further strengthen the notion that mGluR activation significantly contributes to postsynaptic calcium dynamics only following high-frequency stimulation. They also provide a new tool to analyze the interactions between metabotropic and ionotropic glutamate receptors.

Dataset Information

K⁺ efflux through postsynaptic NMDA receptors suppresses local astrocytic glutamate uptake.

Publications

K<sup>+</sup> efflux through postsynaptic NMDA receptors suppresses local astrocytic glutamate uptake.

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