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Astrocytes increase the activity of synaptic GluN2B NMDA receptors

Astrocytes regulate excitatory synapse formation and surface expression of glutamate AMPA receptors (AMPARs) during development. Less is known about glial modulation of glutamate NMDA receptors (NMDARs), which mediate synaptic plasticity and regulate neuronal survival in a subunit- and subcellular l...

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Autores principales: Hahn, Junghyun, Wang, Xianhong, Margeta, Marta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400914/
https://www.ncbi.nlm.nih.gov/pubmed/25941471
http://dx.doi.org/10.3389/fncel.2015.00117
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author Hahn, Junghyun
Wang, Xianhong
Margeta, Marta
author_facet Hahn, Junghyun
Wang, Xianhong
Margeta, Marta
author_sort Hahn, Junghyun
collection PubMed
description Astrocytes regulate excitatory synapse formation and surface expression of glutamate AMPA receptors (AMPARs) during development. Less is known about glial modulation of glutamate NMDA receptors (NMDARs), which mediate synaptic plasticity and regulate neuronal survival in a subunit- and subcellular localization-dependent manner. Using primary hippocampal cultures with mature synapses, we found that the density of NMDA-evoked whole-cell currents was approximately twice as large in neurons cultured in the presence of glia compared to neurons cultured alone. The glial effect was mediated by (an) astrocyte-secreted soluble factor(s), was Mg(2+) and voltage independent, and could not be explained by a significant change in the synaptic density. Instead, we found that the peak amplitudes of total and NMDAR miniature excitatory postsynaptic currents (mEPSCs), but not AMPAR mEPSCs, were significantly larger in mixed than neuronal cultures, resulting in a decreased synaptic AMPAR/NMDAR ratio. Astrocytic modulation was restricted to synaptic NMDARs that contain the GluN2B subunit, did not involve an increase in the cell surface expression of NMDAR subunits, and was mediated by protein kinase C (PKC). Taken together, our findings indicate that astrocyte-secreted soluble factor(s) can fine-tune synaptic NMDAR activity through the PKC-mediated regulation of GluN2B NMDAR channels already localized at postsynaptic sites, presumably on a rapid time scale. Given that physiologic activation of synaptic NMDARs is neuroprotective and that an increase in the synaptic GluN2B current is associated with improved learning and memory, the astrocyte-induced potentiation of synaptic GluN2B receptor activity is likely to enhance cognitive function while simultaneously strengthening neuroprotective signaling pathways.
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spelling pubmed-44009142015-05-04 Astrocytes increase the activity of synaptic GluN2B NMDA receptors Hahn, Junghyun Wang, Xianhong Margeta, Marta Front Cell Neurosci Neuroscience Astrocytes regulate excitatory synapse formation and surface expression of glutamate AMPA receptors (AMPARs) during development. Less is known about glial modulation of glutamate NMDA receptors (NMDARs), which mediate synaptic plasticity and regulate neuronal survival in a subunit- and subcellular localization-dependent manner. Using primary hippocampal cultures with mature synapses, we found that the density of NMDA-evoked whole-cell currents was approximately twice as large in neurons cultured in the presence of glia compared to neurons cultured alone. The glial effect was mediated by (an) astrocyte-secreted soluble factor(s), was Mg(2+) and voltage independent, and could not be explained by a significant change in the synaptic density. Instead, we found that the peak amplitudes of total and NMDAR miniature excitatory postsynaptic currents (mEPSCs), but not AMPAR mEPSCs, were significantly larger in mixed than neuronal cultures, resulting in a decreased synaptic AMPAR/NMDAR ratio. Astrocytic modulation was restricted to synaptic NMDARs that contain the GluN2B subunit, did not involve an increase in the cell surface expression of NMDAR subunits, and was mediated by protein kinase C (PKC). Taken together, our findings indicate that astrocyte-secreted soluble factor(s) can fine-tune synaptic NMDAR activity through the PKC-mediated regulation of GluN2B NMDAR channels already localized at postsynaptic sites, presumably on a rapid time scale. Given that physiologic activation of synaptic NMDARs is neuroprotective and that an increase in the synaptic GluN2B current is associated with improved learning and memory, the astrocyte-induced potentiation of synaptic GluN2B receptor activity is likely to enhance cognitive function while simultaneously strengthening neuroprotective signaling pathways. Frontiers Media S.A. 2015-04-17 /pmc/articles/PMC4400914/ /pubmed/25941471 http://dx.doi.org/10.3389/fncel.2015.00117 Text en Copyright © 2015 Hahn, Wang and Margeta. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Hahn, Junghyun
Wang, Xianhong
Margeta, Marta
Astrocytes increase the activity of synaptic GluN2B NMDA receptors
title Astrocytes increase the activity of synaptic GluN2B NMDA receptors
title_full Astrocytes increase the activity of synaptic GluN2B NMDA receptors
title_fullStr Astrocytes increase the activity of synaptic GluN2B NMDA receptors
title_full_unstemmed Astrocytes increase the activity of synaptic GluN2B NMDA receptors
title_short Astrocytes increase the activity of synaptic GluN2B NMDA receptors
title_sort astrocytes increase the activity of synaptic glun2b nmda receptors
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400914/
https://www.ncbi.nlm.nih.gov/pubmed/25941471
http://dx.doi.org/10.3389/fncel.2015.00117
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