Astrocytes increase the activity of synaptic GluN2B NMDA receptors.

Junghyun Hahn,Xianhong Wang,Marta Margeta

doi:10.3389/fncel.2015.00117

Junghyun Hahn, Xianhong Wang + Show 1 more

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https://doi.org/10.3389/fncel.2015.00117

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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 Mg2+ 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.

Highlights

Glial cells play a critical role in the formation and function of excitatory synapses
The mean amplitude of average NMDA glutamate receptors (NMDARs) miniature excitatory postsynaptic currents (mEPSCs) was significantly larger in mixed than neuronal cultures (6.1 ± 0.8 vs. 3.9 ± 0.6 pA, respectively; n = 7, p < 0.05, t-test; Figure 4B), resulting in a decreased AMPA receptors (AMPARs)/NMDAR ratio in mixed cultures. To determine whether this increase in the average NMDAR mEPSC reflects a population of new synapses or an increase in the NMDAR mEPSC component of existing synapses, we examined the AMPAR/NMDAR ratio at individual synapses using kinetics analysis that is based on distinctive inactivation properties of these two types of glutamate receptors, as described previously (Edmonds et al, 1995; Watt et al, 2000)
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

Summary

Introduction

Glial cells play a critical role in the formation and function of excitatory synapses. Much less is known about glial regulation of NMDA glutamate receptors (NMDARs), which together with AMPARs mediate excitatory postsynaptic signaling. Astrocytic regulation of NMDA receptors is implicated in many neurologic and psychiatric disorders (Cull-Candy et al, 2001; Hardingham and Bading, 2003; Schwartz et al, 2012), highlighting the importance of the precise regulation of NMDAR activity. NMDAR functional diversity is controlled through two distinct mechanisms: subunit composition and subcellular localization (Paoletti et al, 2013; Sanz-Clemente et al, 2013). Of the subunit composition, NMDAR coupling to intracellular signaling cascades depends on the receptor subcellular localization. Non-physiologic (tonic) activation of synaptic NMDARs can lead to excitotoxicity (Parsons and Raymond, 2014), these receptors preferentially couple to neuroprotective signaling pathways when activated by physiologic (phasic) stimuli (Hardingham and Bading, 2010; Martel et al, 2012). Activation of extrasynaptic NMDARs is generally neurotoxic and has been implicated in the pathogenesis of several neurodegenerative disorders (Parsons and Raymond, 2014)

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