Neuronal d-Serine and Glycine Release Via the Asc-1 Transporter Regulates NMDA Receptor-Dependent Synaptic Activity

Rosenberg, Dina; Artoul, Samar; Segal, Adi C.; Kolodney, Goren; Radzishevsky, Inna; Dikopoltsev, Elena; Foltyn, Veronika N.; Inoue, Ran; Mori, Hisashi; Billard, Jean‐Marie; Wolosker, Herman

doi:10.1523/jneurosci.3836-12.2013

Cited by 195 publications

(262 citation statements)

References 44 publications

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“…6 D and E). To confirm that this protective effect was mediated by eNMDARs, we used a second approach to inhibit eNMDARs vs. sNMDARs by bathing hippocampal slices in glycine and D-serine-degrading enzymes (44,45,57). We found that only inhibition of eNMDARs with glycine oxidase significantly protected from spine loss induced by oligomerized Aβ (Fig.…”

Section: Extrasynaptic Nmdars Mediate Aβ-induced Molecular Cascadesmentioning

confidence: 80%

“…Thus, by degrading glycine in slice preparations, the enzyme glycine oxidase (GO) can inhibit eNMDAR-mediated responses. In contrast, enzymes that degrade D-serine, such as D-amino acid oxidase (DAAO) or Dserine deaminase (DsdA), can inhibit sNMDAR-mediated responses (44,45). We used this approach to provide further proof that the basal inward current seen in the hAPP-J20 slices (and associated with our measurement of extracellular glutamate in these mice by HPLC) is caused by eNMDAR activity, because GO but not DAAO largely blocked this current (Fig.…”

Section: Aβ Increases Extrasynaptic Glutamatergic Currents But Decreasesmentioning

confidence: 94%

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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.

502

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: Extrasynaptic Nmdars Mediate Aβ-induced Molecular Cascadesmentioning

confidence: 80%

Section: Aβ Increases Extrasynaptic Glutamatergic Currents But Decreasesmentioning

confidence: 94%

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.

502

524

View full text Add to dashboard Cite

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“…The relevance of this report to NMDAR currents in vivo is therefore contingent upon the NMDAR GLY site being unsaturated in brain tissue. Nonsaturation of the NMDAR GLY site in vivo has been suggested previously (Bergeron et al 1998;Chen et al 2003;Martina et al 2003Martina et al , 2004Wilcox et al 1996), despite the fact that GLY and the other NMDAR coagonist D-serine are both present in some brain regions (Papouin et al 2012;Rosenberg et al 2013;Schell et al 1997). Using glutamate uncaging in acute hippocampal slices, we find that the NMDAR responses from CA1 neurons show desensitization upon glutamate uncaging that is significantly reduced by exposure to HCY.…”

Section: Discussionmentioning

confidence: 46%

“…J Neurophysiol 110: 1567-1582, 2013. First published July 17, 2013 doi:10.1152/jn.00809.2012.-N-methyl-D-aspartate receptors (NMDARs) have been linked to schizophrenia because agents that bind the receptor, like ketamine and phencyclidine, are capable of inducing schizophrenia-like symptoms.…”

mentioning

confidence: 99%

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Bolton

Phillips

Constantine‐Paton

2013

Journal of Neurophysiology

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Bolton AD, Phillips MA, Constantine-Paton M. Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition. J Neurophysiol 110: 1567-1582, 2013. First published July 17, 2013 doi:10.1152/jn.00809.2012.-N-methyl-D-aspartate receptors (NMDARs) have been linked to schizophrenia because agents that bind the receptor, like ketamine and phencyclidine, are capable of inducing schizophrenia-like symptoms. Here we show that the amino acid homocysteine (HCY), which is increased in the blood of schizophrenia patients, reduces desensitization of NMDARs in cultured mouse neurons, human embryonic kidney cells transfected with GluN1 ϩ GluN2A, GluN2B, or GluN2D subunits, and hippocampal slices. HCY also alters the peak amplitude of NMDAR currents, depending on the GluN2 subunit the receptor contains; GluN1 ϩ GluN2A-containing NMDARs show an increase in peak amplitude when exposed to HCY, while GluN1 ϩ GluN2B-containing NMDARs show a decrease in peak amplitude. Both peak amplitude and desensitization effects of HCY can be occluded by saturating the NMDAR with glycine. Since glycine concentrations are not saturating in the brain, HCY could play an NMDAR-modulating role in the nervous system. We also show that HCY shares characteristics with glutamate and suggest that HCY affects both the agonist and coagonist site of the NMDAR.

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“…While our studies did not specifically evaluate D-serine, recent evidence indicates that both D-serine and glycine are synaptic NMDAR coagonists in the CA1 region. However, D-serine appears to be the more important coagonist for LTP induction (Rosenberg et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of N-Methyl-d-Aspartate Receptor–Mediated Excitatory Postsynaptic Potentials and Synaptic Plasticity to TCN 201 and TCN 213 in Rat Hippocampal Slices

Izumi¹,

Zorumski²

2014

J Pharmacol Exp Ther

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Whereas ifenprodil has been used as a selective GluN1/GluN2B (NR1/NR2B, B-type) receptor antagonist to distinguish between GluN2B (NR2B) and GluN2A (NR2A)-containing N-methyl-Daspartate receptors (NMDARs), Contrary to this prediction, inhibition of NMDAR EPSPs by the TCN compounds and ifenprodil were largely overlapping in the CA1 region of hippocampal slices from 30-day-old rats. After partial inhibition by ifenprodil, TCN compounds produced little further suppression of NMDAR EPSPs. Similarly, after partial inhibition by TCN compounds ifenprodil failed to further suppress NMDAR EPSPs. However, low micromolar D-2-amino-5-phosphonovalerate, a competitive NMDAR antagonist, which alone only partially inhibits NMDAR EPSPs, markedly suppresses residual NMDAR responses in the presence of ifenprodil or the TCNs, suggesting that low 2-amino-5-phosphonovalerate antagonizes both ifenprodil-and TCN-insensitive synaptic NMDARs. These observations can be most readily interpreted if ifenprodil and TCNs act on a similar population of synaptic NMDARs. Recent lines of evidence suggest that the majority of hippocampal synaptic NMDARs are triheteromers. If so, modulation of GluN2A, and not just GluN2B NMDARs, could dampen long-term depression (LTD). Indeed, both TCNs, like ifenprodil, blocked LTD, suggesting the involvement of ifenprodil-and TCN-sensitive NMDARs in LTD induction. However, the TCNs plus ifenprodil failed to inhibit long-term potentiation (LTP), suggesting that neither ifenprodil-nor TCN-sensitive NMDARs are essential for LTP induction.

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Neuronal d-Serine and Glycine Release Via the Asc-1 Transporter Regulates NMDA Receptor-Dependent Synaptic Activity

Cited by 195 publications

References 44 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

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Sensitivity of N-Methyl-d-Aspartate Receptor–Mediated Excitatory Postsynaptic Potentials and Synaptic Plasticity to TCN 201 and TCN 213 in Rat Hippocampal Slices

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