NR2B Subunit Exerts a Critical Role in Postischemic Synaptic Plasticity

Picconi, Barbara; Tortiglione, Anna; Barone, Ilaria; Centonze, Diego; Gardoni, Fabrizio; Gubellini, Paolo; Bonsi, Paola; Pisani, Antonio; Bernardi, Giorgio; Luca, Monica Di; Calabresi, Paolo

doi:10.1161/01.str.0000226981.57777.b0

Cited by 66 publications

(50 citation statements)

References 20 publications

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“…23,24 As a matter of fact, in mature cortical cultures and in rats subjected to brain ischemia, activation of either synaptic or extrasynaptic NR2B-containing NMDARs results in excitotoxicity and neuronal apoptosis. 25 The ability of short pulses of C-tDCS to lower the excess of cortical glutamate in healthy mice prompted us to explore whether or not such stimulation protocol might have a neuroprotective role in the very early phase of ischemic stroke, which is characterized by overt glutamatergic excitotoxicity. 12 We thus tested our protocol in mice undergoing 90-minute MCAO.…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Transcranial Direct Current Stimulation in Acute Experimental Ischemic Stroke

Peruzzotti-Jametti

Cambiaghi

Bacigaluppi

et al. 2013

Stroke

119

151

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Background and Purpose— Transcranial direct current stimulation is emerging as a promising tool for the treatment of several neurological conditions, including cerebral ischemia. The therapeutic role of this noninvasive treatment is, however, limited to chronic phases of stroke. We thus ought to investigate whether different stimulation protocols could also be beneficial in the acute phase of experimental brain ischemia. Methods— The influence of both cathodal and anodal transcranial direct current stimulation in modifying brain metabolism of healthy mice was first tested by nuclear magnetic resonance spectroscopy. Then, mice undergoing transient proximal middle cerebral artery occlusion were randomized and treated acutely with anodal, cathodal, or sham transcranial direct current stimulation. Brain metabolism, functional outcomes, and ischemic lesion volume, as well as the inflammatory reaction and blood brain barrier functionality, were analyzed. Results— Cathodal stimulation was able, if applied in the acute phase of stroke, to preserve cortical neurons from the ischemic damage, to reduce inflammation, and to promote a better clinical recovery compared with sham and anodal treatments. This finding was attributable to the significant decrease of cortical glutamate, as indicated by nuclear magnetic resonance spectroscopy. Conversely, anodal stimulation induced an increase in the postischemic lesion volume and augmented blood brain barrier derangement. Conclusions— Our data indicate that transcranial direct current stimulation exerts a measurable neuroprotective effect in the acute phase of stroke. However, its timing and polarity should be carefully identified on the base of the pathophysiological context to avoid potential harmful side effects.

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Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Transcranial Direct Current Stimulation in Acute Experimental Ischemic Stroke

Peruzzotti-Jametti

Cambiaghi

Bacigaluppi

et al. 2013

Stroke

119

151

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“…NR2B-selective antagonists are neuroprotective in a diversity of animal models of neuronal injury (O'Mahony et al, 1998;Picconi et al, 2006), and NR2A C-terminal truncated mutant mice displayed a lesser sensitivity to focal ischemia than wild-type mice (Morikawa et al, 1998). Furthermore, Ser1232 phosphorylation of NR2A subunit catalyzed by cyclin-dependent kinase 5 was found to be involved in selective neuronal death in CA1 region of hippocampus induced by transient global ischemia (Morikawa et al, 1998;Wang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Qian

He²,

Hu³

et al. 2007

J. Neurosci.

140

103

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Fleeting activation of NMDA receptors (NMDARs) induces long-term modification of synaptic connections and refinement of neuronal circuits, which may underlie learning and memory and contribute to pathogenesis of a diversity of neurological diseases, including epilepsy. Here, we found that NR2A and NR2B subunit-containing NMDARs were coupled to distinct intracellular signaling, resulting in differential BDNF expression and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Selective activation of NR2A-containing NMDARs increased BDNF gene expression. Activation of NR2B-containing NMDARs led to ERK1/2 phosphorylation. Furthermore, selectively blocking NR2A-containing NMDARs impaired epileptogenesis and the development of mossy fiber sprouting in the kindling and pilocarpine rat models of limbic epilepsy, whereas inhibiting NR2B-containing NMDARs had no effects in epileptogenesis and mossy fiber sprouting. Interestingly, blocking either NR2A- or NR2B-containing NMDARs decreased status epilepticus-induced neuronal cell death. The specific requirement of NR2A and its downstream signaling for epileptogenesis implicates attractive new targets for the development of drugs that prevent epilepsy in patients with brain injury.

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“…24,25 In Vivo Middle Cerebral Artery Occlusion Ischemia Model Transient cerebral focal ischemia was produced by middle cerebral artery occlusion (MCAO) as reported previously. 17,26 -28 Briefly, male Sprague Dawley rats (280 -300 g) were anesthetized, and MCAO was produced by occluding the MCA with a monofilament suture.…”

Section: Oxygen-glucose-deprivation-induced Ischemia Modelmentioning

confidence: 99%

Glycine Exerts Dual Roles in Ischemic Injury Through Distinct Mechanisms

Yao

Ji²,

Zheng³

et al. 2012

Stroke

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Background and Purpose-We characterized the differential effects of glycine at different levels in the induction of postischemic long-term potentiation, as well as in the neuronal damage induced by focal ischemia. Methods-Whole-cell patch clamp recordings were obtained from rat hippocampal slice preparations. In vitro ischemia and postischemic long-term potentiation were induced by oxygen and glucose deprivation. In vivo ischemia was induced by transient middle cerebral artery occlusion. Results-In both in vitro and in vivo ischemia models, glycine at low level exerts deleterious effects in postischemic long-term potentiation and ischemic neuronal injury by modulation of the N-methyl-D-aspartate receptor coagonist site; whereas glycine at high level exerts neuroprotective effects by activation of glycine receptor and subsequent differential regulation of N-methyl-D-aspartate receptor subunit components. Conclusions-Our results provide a molecular basis for the dual roles of glycine in ischemic injury through distinct mechanisms, and they suggest that glycine receptors could be a potential target for clinical treatment of stroke. (Stroke. 2012;43:2212-2220.)Key Words: glycine Ⅲ ischemia Ⅲ electrophysiology Ⅲ middle cerebral artery occlusion Ⅲ N-methyl-D Ⅲ aspartate receptor A pathological form of plasticity, named postischemic long-term potentiation (i-LTP), was observed in glutamatereceptor-mediated neurotransmission after stroke. [1][2][3] There is evidence that i-LTP in the hippocampus may exert a detrimental effect via facilitation of excitotoxic damage. 3 This long-term enhancement in AMPA-and NMDA-receptor-mediated excitatory responses was mainly attributable to overstimulation of glutamatergic neurotransmission by excessively released extracellular glutamate in the postischemic brain. Given that overexcitation of neurons caused by stroke disturbs the balance between excitation and inhibition, restoring this balance via intervention with additional inhibition seems to be a potential and practical strategy.Ischemia elicits the rapid release of various amino acid neurotransmitters, including glycine. 4,5 Glycine is a 2-faceted bioactive molecule in the central nervous system. 6 Glycine is a strychnine-insensitive coagonist for N-methyl-D-aspartate receptors (NMDAR) and is essential for activation of NMDARs. [7][8][9] And yet, glycine is one of the main inhibitory neurotransmitters in the central nervous system. 10 Over the past decade, accumulating evidence has suggested that functional glycine receptors are present throughout all regions in the hippocampus, and they play an important role in regulating excitability and plasticity. These strychnine-sensitive glycine receptors (GlyR), if located postsynaptically, are mostly in extrasynaptic sites. 11 Because GlyRs activation induces Cl Ϫ flux and neuronal hyperpolarization, and thus suppresses neuronal excitability, we sought to determine whether and how activation of extrasynaptic GlyRs could help restore excitation-inhibition balance and activity-dependent p...

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NR2B Subunit Exerts a Critical Role in Postischemic Synaptic Plasticity

Cited by 66 publications

References 20 publications

Safety and Efficacy of Transcranial Direct Current Stimulation in Acute Experimental Ischemic Stroke

Safety and Efficacy of Transcranial Direct Current Stimulation in Acute Experimental Ischemic Stroke

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Glycine Exerts Dual Roles in Ischemic Injury Through Distinct Mechanisms

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