Reverse glial glutamate uptake triggers neuronal cell death through extrasynaptic NMDA receptor activation

Gouix, Elsa; Léveillé, Frédéric; Nicole, Olivier; Melon, Christophe; Had‐Aissouni, Laurence; Buisson, Alain

doi:10.1016/j.mcn.2009.01.002

Cited by 72 publications

(65 citation statements)

References 51 publications

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“…Treatment with low concentrations of memantine protects against NMDA-induced toxicity in vitro Papadia et al, 2008;Gouix et al, 2009;Bordji et al, 2010), as well as neurotoxicity and learning deficits in chemical lesion models (Misztal et al, 1996;Lee et al, 2006) and neurodegenerative disease models (Okamoto et al, 2009;Martinez-Coria et al, 2010;. However, higher doses of memantine produce deleterious effects (Chen et al, 1998;Chen and Lipton, 2006;Okamoto et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, extrasynaptic NMDARs shut off cell survival pathways (Hardingham et al, 2002), induce mitochondrial dysfunction (Gouix et al, 2009), and activate pro-death molecules (Léveillé et al, 2010). Thus far, disparate synaptic/extrasynaptic NMDAR signaling has been investigated in cortical (CTX) and hippocampal neurons; it is unknown whether nonglutamatergic subcortical projection neurons, such as GABAergic medium-sized spiny projection neurons of the striatum (MSNs; Ͼ90% of striatal cells), follow the same pattern.…”

Section: Introductionmentioning

confidence: 99%

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Opposing Roles of Synaptic and Extrasynaptic NMDA Receptor Signaling in Cocultured Striatal and Cortical Neurons

Kaufman

Milnerwood²,

Sepers³

et al. 2012

J. Neurosci.

115

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The NMDAR plays a unique and vital role in subcellular signaling. Calcium influx initiates signaling cascades important for both synaptic plasticity and survival; however, overactivation of the receptor leads to toxicity and cell death. This dichotomy is partially explained by the subcellular location of the receptor. NMDARs located at the synapse stimulate cell survival pathways, while extrasynaptic receptors signal for cell death. Thus far, this interplay between synaptic and extrasynaptic NMDARs has been studied exclusively in cortical (CTX) and hippocampal neurons. It was unknown whether other cell types, such as GABAergic medium-sized spiny projection neurons of the striatum (MSNs), which bear the brunt of neurodegeneration in Huntington's disease, follow the same pattern. Here we report synaptic versus extrasynaptic NMDAR signaling in striatal MSNs and resultant activation of cAMP response element binding protein (CREB), in rat primary corticostriatal cocultures. Similarly to CTX, we found in striatal MSNs that synaptic NMDARs activate CREB, whereas extrasynaptic NMDARs dominantly oppose CREB activation. However, MSNs are much less susceptible to NMDA-mediated toxicity than CTX cells and show differences in subcellular GluN2B distribution. Blocking NMDARs with memantine (30 M) or GluN2B-containing receptors with ifenprodil (3 M) prevents CREB shutoff effectively in CTX and MSNs, and also rescues both neuronal types from NMDA-mediated toxicity. This work may provide cell and NMDAR subtype-specific targets for treatment of diseases with putative NMDAR involvement, including neurodegenerative disorders and ischemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Opposing Roles of Synaptic and Extrasynaptic NMDA Receptor Signaling in Cocultured Striatal and Cortical Neurons

Kaufman

Milnerwood²,

Sepers³

et al. 2012

J. Neurosci.

115

View full text Add to dashboard Cite

show abstract

“…To activate synaptic NMDARs, we used a stimulation paradigm that we have previously characterized on cortical neurons (Gouix et al, 2009). Coapplication of bicuculline (50 M), a GABAA receptor antagonist, and 4AP (2.5 mM), a weak potassium-channel blocker, induces synchronous bursts of action potentials leading to synaptic NMDAR activation (Hardingham and Bading, 2002).…”

Section: Synaptic Nmdar Activationmentioning

confidence: 99%

“…Immunocytochemistry was performed as described by Gouix et al (2009). To evaluate the proportion of p-ERK-positive neurons, we performed colabeling for p-ERK (1:100; Santa Cruz Biotechnology) and a neuronal marker (1:500; Sigma-Aldrich).…”

Section: Immunocytochemistrymentioning

confidence: 99%

Interaction Between CaMKII and GluN2B Controls ERK-Dependent Plasticity

Gaamouch

Buisson²,

Moustié³

et al. 2012

Journal of Neuroscience

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Understanding how brief synaptic events can lead to sustained changes in synaptic structure and strength is a necessary step in solving the rules governing learning and memory. Activation of ERK1/2 (extracellular signal regulated protein kinase 1/2) plays a key role in the control of functional and structural synaptic plasticity. One of the triggering events that activates ERK1/2 cascade is an NMDA receptor (NMDAR)-dependent rise in free intracellular Ca 2ϩ concentration. However the mechanism by which a short-lasting rise in Ca 2ϩ concentration is transduced into long-lasting ERK1/2-dependent plasticity remains unknown. Here we demonstrate that although synaptic activation in mouse cultured cortical neurons induces intracellular Ca 2ϩ elevation via both GluN2A and GluN2B-containing NMDARs, only GluN2B-containing NMDAR activation leads to a long-lasting ERK1/2 phosphorylation. We show that ␣CaMKII, but not ␤CaMKII, is critically involved in this GluN2B-dependent activation of ERK1/2 signaling, through a direct interaction between GluN2B and ␣CaMKII. We then show that interfering with GluN2B/␣CaMKII interaction prevents synaptic activity from inducing ERKdependent increases in synaptic AMPA receptors and spine volume. Thus, in a developing circuit model, the brief activity of synaptic GluN2B-containing receptors and the interaction between GluN2B and ␣CaMKII have a role in long-term plasticity via the control of ERK1/2 signaling. Our findings suggest that the roles that these major molecular elements have in learning and memory may operate through a common pathway.

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“…Many studies have established that synaptic NMDAR activation induced an upregulation of key pathways (ERK, CaMK), transcription factors (CREB), or prosurvival genes (BDNF). Conversely, activation of extrasynaptic NMDAR was shown to cause a loss of mitochondrial membrane potential (Hardingham et al, 2002;Léveillé et al, 2008;Gouix et al, 2009), and to have opposite effects on synaptic NMDAR-activated CREB function (Hardingham et al, 2002;Soriano and Hardingham, 2007;Mulholland et al, 2008), ERK pathway (Ivanov et al, 2006;Gouix et al, 2009), or BDNF expression (Vanhoutte and Bading, 2003). Very recently, extrasynaptic NMDARs were also shown to be implicated in the pathogenesis of Huntington's disease (Okamoto et al, 2009;Milnerwood et al, 2010).…”

mentioning

confidence: 99%

Activation of Extrasynaptic, But Not Synaptic, NMDA Receptors Modifies Amyloid Precursor Protein Expression Pattern and Increases Amyloid-β Production

Bordji¹,

Becerril-Ortega²,

Nicole³

et al. 2010

J. Neurosci.

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167

147

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Calcium is a key mediator controlling essential neuronal functions depending on electrical activity. Altered neuronal calcium homeostasis affects metabolism of amyloid precursor protein (APP), leading to increased production of ␤-amyloid (A␤), and contributing to the initiation of Alzheimer's disease (AD). A linkage between excessive glutamate receptor activation and neuronal A␤ release was established, and recent reports suggest that synaptic and extrasynaptic NMDA receptor (NMDAR) activation may have distinct consequences in plasticity, gene regulation, and neuronal death. Here, we report for the first time that prolonged activation of extrasynaptic NMDAR, but not synaptic NMDAR, dramatically increased the neuronal production of A␤. This effect was preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing APPs (KPI-APPs), isoforms exhibiting an important amyloidogenic potential. Conversely, after synaptic NMDAR activation, we failed to detect any KPI-APP expression and neuronal A␤ production was not modified. Calcium imaging data showed that intracellular calcium concentration after extrasynaptic NMDAR stimulation was lower than after synaptic activation. This suggests distinct signaling pathways for each pool of receptors. We found that modification of neuronal APP expression pattern triggered by extrasynaptic NMDAR activation was regulated at an alternative splicing level involving calcium-/ calmodulin-dependent protein kinase IV, but overall APP expression remained identical. Finally, memantine dose-dependently inhibited extrasynaptic NMDAR-induced KPI-APPs expression as well as neuronal A␤ release. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR promotes amyloidogenic KPI-APP expression leading to neuronal A␤ release, representing a causal risk factor for developing AD.

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Reverse glial glutamate uptake triggers neuronal cell death through extrasynaptic NMDA receptor activation

Cited by 72 publications

References 51 publications

Opposing Roles of Synaptic and Extrasynaptic NMDA Receptor Signaling in Cocultured Striatal and Cortical Neurons

Opposing Roles of Synaptic and Extrasynaptic NMDA Receptor Signaling in Cocultured Striatal and Cortical Neurons

Interaction Between CaMKII and GluN2B Controls ERK-Dependent Plasticity

Activation of Extrasynaptic, But Not Synaptic, NMDA Receptors Modifies Amyloid Precursor Protein Expression Pattern and Increases Amyloid-β Production

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