D‐Serine‐induced Inactivation of <scp>NMDA</scp> Receptors in Cultured Rat Hippocampal Neurons Expressing <scp>NR</scp>2A Subunits is Ca<sup>2+</sup>‐Dependent

Li, Xia; Zhang, Yuanyuan; Chen, Zhao-Qin; Jiang, Zheng‐Lin; Sun, Lixia; Xu, Lihua; Yang, Yanling; Zhang, Yunfeng

doi:10.1111/cns.12308

Cited by 4 publications

(4 citation statements)

References 44 publications

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“…D-serine is a preferential co-agonist of NR2A-containing NMDARs, and we wanted to verify the hypothesis that it could be involved in CX3CL1-induced neuroprotective effects. Although in vitro systems do not allow to distinguish between synaptic and extrasynaptic NMDAR, cultured hippocampal neurons do express both NR2A and NR2B subunits (Li et al, 2014 ) and can be used to investigate the effects of both kinds of NMDARs. In this paper we report data showing that: (i) NMDA-induced excitotoxicity is prevented by CX3CL1 with mechanisms involving A 2A R; (ii) D-serine mediates the neuroprotective effect of CX3CL1 against NMDA- but not Glu-toxicity; (iii) CX3CL1 and D-serine phosphorylate CREB with a mechanism involving the presence of A 2A R. Adenosine is a metabolite that acts through different receptor subtypes (Jacobson and Gao, 2006 ); among them A 1 R (Lauro et al, 2008 , 2010 ) and A 3 R (Rosito et al, 2014 ) are involved in CX3CL1 neuroprotection against Glu-induced toxicity.…”

Section: Discussionmentioning

confidence: 99%

Fractalkine/CX3CL1 engages different neuroprotective responses upon selective glutamate receptor overactivation

Lauro

Catalano

Paolo

et al. 2015

Front. Cell. Neurosci.

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Neuronal death induced by overactivation of N-methyl-d-aspartate receptors (NMDARs) is implicated in the pathophysiology of many neurodegenerative diseases such as stroke, epilepsy and traumatic brain injury. This toxic effect is mainly mediated by NR2B-containing extrasynaptic NMDARs, while NR2A-containing synaptic NMDARs contribute to cell survival, suggesting the possibility of therapeutic approaches targeting specific receptor subunits. We report that fractalkine/CX3CL1 protects hippocampal neurons from NMDA-induced cell death with a mechanism requiring the adenosine receptors type 2A (A2AR). This is different from CX3CL1-induced protection from glutamate (Glu)-induced cell death, that fully depends on A1R and requires in part A3R. We show that CX3CL1 neuroprotection against NMDA excitotoxicity involves D-serine, a co-agonist of NR2A/NMDAR, resulting in cyclic AMP-dependent transcription factor cyclic-AMP response element-binding protein (CREB) phosphorylation.

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Section: Discussionmentioning

confidence: 99%

Fractalkine/CX3CL1 engages different neuroprotective responses upon selective glutamate receptor overactivation

Lauro

Catalano

Paolo

et al. 2015

Front. Cell. Neurosci.

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“…receptors. [80] Ischemia also stimulates neurons to release Zn. [81] This ion also interacts with the external domain of GluN2A and GluN2B receptors and, like D-serine, its impact differs depending on receptor composition.…”

Section: Ischemic Conditions Shift Activity To Ca-ampar and Glun2b Receptorsmentioning

confidence: 99%

“…At elevated levels of receptor stimulation D‐serine reduces the flow of Ca through GluN2A receptors, but has little impact on the flow through GluN2B receptors. [ 80 ] Ischemia also stimulates neurons to release Zn. [ 81 ] This ion also interacts with the external domain of GluN2A and GluN2B receptors and, like D‐serine, its impact differs depending on receptor composition.…”

Section: Extracellular Glutamate May Stimulate Ischemic Neurons To Import and Oxidize Glutamatementioning

confidence: 99%

A beneficial role for elevated extracellular glutamate in Amyotrophic Lateral Sclerosis and cerebral ischemia

Schiel

2021

BioEssays

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This hypothesis proposes that increased extracellular glutamate in Amyotrophic Lateral Sclerosis (ALS) and cerebral ischemia, currently viewed as a trigger for excitotoxicity, is actually beneficial as it stimulates the utilization of glutamate as metabolic fuel.Renewed appreciation of glutamate oxidation by ischemic neurons has raised questions regarding the role of extracellular glutamate in ischemia. Is it detrimental, as suggested by excitotoxicity in early in vitro studies, or beneficial, as suggested by its oxidation in later in vivo studies? The answer may depend on the activity of N-methyl-Daspartate (NMDA) glutamate receptors. Early in vitro procedures co-activated NMDA receptors (NMDARs) containing 2A (GluN2A) and 2B (GluN2B) subunits, an event now believed to trigger excitotoxicity; however, during in vivo ischemia D-serine and zinc molecules are released and these ensure only GluN2B receptors are stimulated. This not only prevents excitotoxicity but also initiates signaling cascades that allow ischemic neurons to import and oxidize glutamate.

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“…NMDA receptors require the NR1 subunit as a necessary component to generate typical NMDA-specific currents [183], and have NR2 subunits with cell-type specific intracellular C-terminal domains that alter channel kinetics [184]. The activity-dependent ratio of NR2A/NR2B is vital to cortical functioning [185], and in response to increased activation of NMDA receptors, NR2A subunits are decreased concurrently with receptor activity [186] (an effect that is Ca2+ dependent [187]). These subunits can also be increased by blockade of iGluRs and/or cell activity [188], indicating that down-regulation of these subunits may be protective against the harmful effects of increased glutamatergic transmission.…”

Section: Introductionmentioning

confidence: 99%

Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

Summers¹

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DEDICATIONTo my mother Andrea, who through her example taught me that the values of hard work, integrity, and good manners never go out of style To Karen, who taught me the true meaning of courage under the threat of certain death, and that those no longer with us physically continue to live in our thoughts iv ACKNOWLEDGEMENTS All information and data in this text was only possible due to the generous support and inexhaustible patience of my advisor Jeff Steketee and my graduate committee (which included Drs. John Boughter, Michael McDonald, Kazuko Sakata, and Wen Lin Sun). Also, instrumental to the completion of this project were the helping hands of Dr. Steve Tavalin. This project also could have never been completed without financial support from the University of Tennessee Health Science Center Neuroscience Institute and the National Institute on Drug Abuse (NIDA).v ABSTRACT Towards the goal of improving the knowledge base of how drugs of abuse function to create addicts and using currently uninvestigated areas of this knowledge base, we focused our research studies the male albino rat, and strived to explain how cocaine sensitization alters particular molecular mechanisms in the mesocorticolimbic system related to glutamate receptors, SAPAPs, and affects drug self-administration. Taking all the previously discussed research studies into consideration, we hypothesized that low-dose cocaine self-administration would yield a significant elevation in drug seeking behavior for psychostimulant sensitized animals. For specific changes at the PSD, we hypothesized that acute cocaine exposure and/or cocaine sensitization would alter iGluRs levels in the mPFC, and SAPAP levels in multiple sites of the mesocorticolimbic system. To test these hypotheses, we investigated the effects of psychostimulant sensitization on various parameters of self-administration by infusing a low-dose cocaine reward proven to not induce sensitization during self-administration (reported here as 0.3 mg/kg/infusion). Although drug exposure did not significantly alter self-administration behavior, we did find that more drug exposed subjects acquired selfadministration behavior when compared to drug naïve controls. We also investigated the effects of acute cocaine exposure and/or cocaine sensitization on iGluRs in the mPFC and SAPAPs in the entire mesocorticolimbic circuit thru western blotting, immunolabeling of proteins of interest, and comparing protein levels to those found in cocaine naïve controls. A limited self-administration protocol also tested if SAPAP levels were altered by self-administration of a low-dose cocaine reward. For these experiments, we found that SAPAP protein levels are altered in multiple regions of the mesocorticolimbic system in response to contingent and non-contingent cocaine exposure, and that iGluR receptor subunits are altered in the prefrontal cortex in response to non-contingent cocaine exposure. vi PREFACEThe Incans that first cultivated the coca plant for medicinal use five millennia ago reserved this "Elix...

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D‐Serine‐induced Inactivation of NMDA Receptors in Cultured Rat Hippocampal Neurons Expressing NR2A Subunits is Ca²⁺‐Dependent

Abstract: D-serine can also induce inactivation of NMDARs, the NR2A subunit is required for the induction of this effect, and this inactivation is Ca(2+)-dependent in nature. This action of D-serine is hypothesized to play a neuroprotective role upon a sustained large glutamate insult to the brain.

Cited by 4 publications

References 44 publications

Fractalkine/CX3CL1 engages different neuroprotective responses upon selective glutamate receptor overactivation

Fractalkine/CX3CL1 engages different neuroprotective responses upon selective glutamate receptor overactivation

A beneficial role for elevated extracellular glutamate in Amyotrophic Lateral Sclerosis and cerebral ischemia

Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

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D‐Serine‐induced Inactivation of NMDA Receptors in Cultured Rat Hippocampal Neurons Expressing NR2A Subunits is Ca2+‐Dependent

Abstract: D-serine can also induce inactivation of NMDARs, the NR2A subunit is required for the induction of this effect, and this inactivation is Ca(2+)-dependent in nature. This action of D-serine is hypothesized to play a neuroprotective role upon a sustained large glutamate insult to the brain.

Cited by 4 publications

References 44 publications

Fractalkine/CX3CL1 engages different neuroprotective responses upon selective glutamate receptor overactivation

Fractalkine/CX3CL1 engages different neuroprotective responses upon selective glutamate receptor overactivation

A beneficial role for elevated extracellular glutamate in Amyotrophic Lateral Sclerosis and cerebral ischemia

Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

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Product

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D‐Serine‐induced Inactivation of NMDA Receptors in Cultured Rat Hippocampal Neurons Expressing NR2A Subunits is Ca²⁺‐Dependent