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Astrocytes increase the activity of synaptic GluN2B NMDA receptors.

Hahn J, Wang X, Margeta M - Front Cell Neurosci (2015)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of California San Francisco San Francisco, CA, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Model for astrocyte-mediated regulation of neuronal NMDARs. (A) When hippocampal neurons are cultured in the absence of glia, glutamate released from the presynaptic terminal activates both GluN2A and GluN2B NMDARs localized at synapses. (B) In the presence of glia, astrocytes secrete a currently unidentified soluble factor or factors (blue arrow) that activate PKC. Through phosphorylation of either the GluN2B subunit itself (solid green arrow) or, more likely, an ancillary protein (X) associated with the NMDAR signaling complex (dashed red arrows), PKC activation leads to an increase in the activity of synaptic GluN2B NMDARs without affecting the activity of either synaptic GluN2A NMDARs or extrasynaptic GluN2B NMDARs; it remains to be seen whether astrocytic modulation is specific for GluN1/2B heterodimers or it also affects GluN1/2A/2B heterotrimers (as shown).
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Figure 11: Model for astrocyte-mediated regulation of neuronal NMDARs. (A) When hippocampal neurons are cultured in the absence of glia, glutamate released from the presynaptic terminal activates both GluN2A and GluN2B NMDARs localized at synapses. (B) In the presence of glia, astrocytes secrete a currently unidentified soluble factor or factors (blue arrow) that activate PKC. Through phosphorylation of either the GluN2B subunit itself (solid green arrow) or, more likely, an ancillary protein (X) associated with the NMDAR signaling complex (dashed red arrows), PKC activation leads to an increase in the activity of synaptic GluN2B NMDARs without affecting the activity of either synaptic GluN2A NMDARs or extrasynaptic GluN2B NMDARs; it remains to be seen whether astrocytic modulation is specific for GluN1/2B heterodimers or it also affects GluN1/2A/2B heterotrimers (as shown).

Mentions: Neuronal NMDARs play a critical role in synaptic plasticity, neuroprotection, and neurotoxicity, but relatively little is known about their regulation by glial cells. Our study identified a novel form of astrocytic NMDAR modulation that occurs in a subunit- and subcellular localization-dependent manner. The density of NMDA-evoked whole-cell current was approximately doubled in neurons cultured in the presence of a mixed population of glia compared to neurons cultured alone (Figure 1), indicating a change in either expression or function of postsynaptic NMDAR channels. The glial effect was mediated by (an) astrocyte-secreted soluble factor(s) (Figure 1), was Mg2+ and voltage independent (Figure 1), and could not be explained by an appreciable change in the synaptic density (Figure 3). Instead, we found that the peak amplitude of total and NMDAR mEPSCs, but not AMPAR mEPSCs, was significantly larger in mixed cultures, resulting in a decreased synaptic AMPAR/NMDAR ratio (Figures 2, 4, 5). Astrocytic modulation was restricted to synaptic NMDARs that contain the GluN2B subunit (Figures 6, 7), did not involve an increase in the cell surface expression of NMDAR subunits (Figure 8), and was mediated by PKC (Figure 9). Collectively, these data show that astrocyte-secreted soluble factor(s) can fine-tune synaptic NMDAR activity through the PKC-mediated regulation of GluN2B NMDAR channels already present at postsynaptic sites, presumably on a rapid time scale (Figure 11).


Astrocytes increase the activity of synaptic GluN2B NMDA receptors.

Hahn J, Wang X, Margeta M - Front Cell Neurosci (2015)

Model for astrocyte-mediated regulation of neuronal NMDARs. (A) When hippocampal neurons are cultured in the absence of glia, glutamate released from the presynaptic terminal activates both GluN2A and GluN2B NMDARs localized at synapses. (B) In the presence of glia, astrocytes secrete a currently unidentified soluble factor or factors (blue arrow) that activate PKC. Through phosphorylation of either the GluN2B subunit itself (solid green arrow) or, more likely, an ancillary protein (X) associated with the NMDAR signaling complex (dashed red arrows), PKC activation leads to an increase in the activity of synaptic GluN2B NMDARs without affecting the activity of either synaptic GluN2A NMDARs or extrasynaptic GluN2B NMDARs; it remains to be seen whether astrocytic modulation is specific for GluN1/2B heterodimers or it also affects GluN1/2A/2B heterotrimers (as shown).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 11: Model for astrocyte-mediated regulation of neuronal NMDARs. (A) When hippocampal neurons are cultured in the absence of glia, glutamate released from the presynaptic terminal activates both GluN2A and GluN2B NMDARs localized at synapses. (B) In the presence of glia, astrocytes secrete a currently unidentified soluble factor or factors (blue arrow) that activate PKC. Through phosphorylation of either the GluN2B subunit itself (solid green arrow) or, more likely, an ancillary protein (X) associated with the NMDAR signaling complex (dashed red arrows), PKC activation leads to an increase in the activity of synaptic GluN2B NMDARs without affecting the activity of either synaptic GluN2A NMDARs or extrasynaptic GluN2B NMDARs; it remains to be seen whether astrocytic modulation is specific for GluN1/2B heterodimers or it also affects GluN1/2A/2B heterotrimers (as shown).
Mentions: Neuronal NMDARs play a critical role in synaptic plasticity, neuroprotection, and neurotoxicity, but relatively little is known about their regulation by glial cells. Our study identified a novel form of astrocytic NMDAR modulation that occurs in a subunit- and subcellular localization-dependent manner. The density of NMDA-evoked whole-cell current was approximately doubled in neurons cultured in the presence of a mixed population of glia compared to neurons cultured alone (Figure 1), indicating a change in either expression or function of postsynaptic NMDAR channels. The glial effect was mediated by (an) astrocyte-secreted soluble factor(s) (Figure 1), was Mg2+ and voltage independent (Figure 1), and could not be explained by an appreciable change in the synaptic density (Figure 3). Instead, we found that the peak amplitude of total and NMDAR mEPSCs, but not AMPAR mEPSCs, was significantly larger in mixed cultures, resulting in a decreased synaptic AMPAR/NMDAR ratio (Figures 2, 4, 5). Astrocytic modulation was restricted to synaptic NMDARs that contain the GluN2B subunit (Figures 6, 7), did not involve an increase in the cell surface expression of NMDAR subunits (Figure 8), and was mediated by PKC (Figure 9). Collectively, these data show that astrocyte-secreted soluble factor(s) can fine-tune synaptic NMDAR activity through the PKC-mediated regulation of GluN2B NMDAR channels already present at postsynaptic sites, presumably on a rapid time scale (Figure 11).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of California San Francisco San Francisco, CA, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus