Memantine Preferentially Blocks Extrasynaptic over Synaptic NMDA Receptor Currents in Hippocampal Autapses

Xia, Peng; Chen, Huei‐Sheng Vincent; Zhang, Dongxian; Lipton, Stuart A.

doi:10.1523/jneurosci.2488-10.2010

Cited by 336 publications

(312 citation statements)

References 39 publications

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“…2 A-C). Prior work had shown that the tonic inward current in this preparation represents activation of extrasynaptic glutamate receptors (3,5,27,28). To confirm this finding, we performed recordings after pharmacological isolation of extrasynaptic currents using the published protocol of first activating excitatory synaptic currents electrically followed by the addition of dizocilpine (MK-801) to block these synaptic responses (29) (Fig.…”

Section: Aβ Increases Extrasynaptic Glutamatergic Currents But Decreasesmentioning

confidence: 74%

“…This preparation allows rapid access of exogenous Aβ and applied drugs to neural tissue and also simultaneous recording of eNMDARs and sNMDARs with a single patch electrode. In hippocampal autaptic cultures, we found that picomolar naturally occurring Aβ-soluble oligomers, nanomolar oligomeric Aβ 1-42 (but not monomeric), or low-micromolar Aβ [25][26][27][28][29][30][31][32][33][34][35] (but not Aβ ) induced a tonic inward current within tens of seconds of application in ∼55% of neurons (Fig. 2 A-G; n = 90).…”

Section: Aβ Increases Extrasynaptic Glutamatergic Currents But Decreasesmentioning

confidence: 95%

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Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Talantova

Sanz-Blasco

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

514

524

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Significance Communication between nerve cells occurs at specialized cellular structures known as synapses. Loss of synaptic function is associated with cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here we describe a pathway for synaptic damage whereby amyloid-β 1–42 peptide (Aβ 1–42 ) releases, via stimulation of α7 nicotinic receptors, excessive amounts of glutamate from astrocytes, in turn activating extrasynaptic NMDA-type glutamate receptors (eNMDARs) to mediate synaptic damage. The Food and Drug Administration-approved drug memantine offers some beneficial effect, but the improved eNMDAR antagonist NitroMemantine completely ameliorates Aβ-induced synaptic loss, providing hope for disease-modifying intervention in AD.

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Section: Aβ Increases Extrasynaptic Glutamatergic Currents But Decreasesmentioning

confidence: 74%

Section: Aβ Increases Extrasynaptic Glutamatergic Currents But Decreasesmentioning

confidence: 95%

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Talantova

Sanz-Blasco

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

514

524

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“…All chemicals were purchased from Sigma. Cdk5 substrate and Aβ [25][26][27][28][29][30][31][32][33][34][35] , Aβ , and Aβ 1-42 peptides were from Anaspec.…”

Section: Methodsmentioning

confidence: 99%

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

Nakamura

Cao

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

169

182

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The activity of Cdk5 and its regulatory subunit p35 is thought to be important in both normal brain function and neurodegenerative disease pathogenesis. Increased Cdk5 activity, via proteolytic cleavage of p35 to a p25 fragment by the calcium-activated protease calpain or by phosphorylation at Cdk5(Tyr15), can contribute to neurotoxicity. Nonetheless, our knowledge of regulation of Cdk5 activity in disease states is still emerging. Here we demonstrate that Cdk5 is activated by S-nitrosylation or reaction of nitric oxide (NO)-related species with the thiol groups of cysteine residues 83 and 157, to form SNO-Cdk5. We then show that S-nitrosylation of Cdk5 contributes to amyloid-β (Aβ) peptide-induced dendritic spine loss. Furthermore, we observed significant levels of SNO-Cdk5 in postmortem Alzheimer's disease (AD) but not in normal human brains. These findings suggest that S-nitrosylation of Cdk5 is an aberrant regulatory mechanism of enzyme activity that may contribute to the pathogenesis of AD.C dk5 is a cyclin-dependent kinase that is activated by proteins p35, p25, and p39 (1-3). As a predominantly neuronalspecific kinase, Cdk5 lacks a role in cell-cycle control but has been implicated in an array of neuronal functions, including cell survival, axon guidance, neuronal migration, and regulation of synaptic spine density (4-6). Dysregulation of Cdk5 activity may play a role in the pathogenesis of stroke and several neurodegenerative disorders, including Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease (7-11). Cdk5 is also hyperactivated in response to oxidative stress, mitochondrial dysfunction, excitotoxicity, amyloid-β (Aβ) exposure, calcium overload, and neuroinflammation, thus contributing to neuronal damage. These neurotoxic stimuli activate calpain, which cleaves the Cdk5 activator p35 (or p39) into p25 (or p29); p25 accumulation thus contributes to Cdk5 activation (12-16). These changes trigger various events associated with neurodegeneration. Although increased Cdk5 activity has been observed in AD brains compared with nondemented control brains, the mechanism remains contentious (17).Similarly, nitric oxide (NO) and related species contribute to a number of neurodegenerative diseases. The major source of NO in neurons is neuronal nitric oxide synthase (NOS1). Excitotoxic stress increases intracellular Ca 2+ , which in turn activates NOS1, thus generating NO. In general, NO can stimulate soluble guanylate cyclase to form cGMP or can S-nitrosylate critical cysteine residues to regulate the activity of multiple target proteins, in some sense akin to phosphorylation. Indeed, S-nitrosylation may explain many cGMP-independent mechanisms of NO action in neurodegenerative diseases (18). Our group has demonstrated that NO contributes to neurodegenerative disorders by redox reaction consisting of S-nitrosylation; in some cases this reaction is followed by further oxidation. Proteins affected in this manner include the gelatinase enzyme matrix metalloprotineas...

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“…The different properties of memantine allow the drug to limit pathological activity of the NMDARs while relatively sparing normal synaptic activity. In fact, different independent papers reported that, unlike other classical NMDAR antagonists (e.g., MK801, AP5), memantine preferentially blocks extrasynaptic over synaptic NMDAR currents in neurons Xia et al , 2010 ). The importance of maintaining normal synaptic NMDA signaling has been interestingly underlined by Papadia et al who showed that synaptic NMDA activity is necessary to boost intrinsic antioxidant defenses (Papadia et al , 2008 ).…”

Section: Targeting Extrasynaptic Nmdars To Lower a β Peptide: Interesmentioning

confidence: 99%

“…The Lipton group fi rst reported that memantine binds at or near the Mg 2 + site in the NMDAR-associated channel and they recently provided evidence explaining the discriminative action of memantine (Xia et al , 2010 ). Under normal conditions, at resting membrane potentials, most NMDARs are blocked by extracellular Mg 2 + , which occupies the channel.…”

Section: Targeting Extrasynaptic Nmdars To Lower a β Peptide: Interesmentioning

confidence: 99%

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Bordji

Becerril-Ortega

2011

Revneuro

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A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β , contributing to the initiation of Alzheimer ' s disease. Among the different routes of Ca 2 + entry, N -methyld -aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca 2 + infl ux. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer ' s disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia.

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Memantine Preferentially Blocks Extrasynaptic over Synaptic NMDA Receptor Currents in Hippocampal Autapses

Cited by 336 publications

References 39 publications

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

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