Targeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases
Abstract
1. Introduction
2. Physiology of NMDA Receptors
2.1. Structure, Composition, and Localization
2.2. NMDARs in the Glutamatergic Synapse
2.3. Regulation of NMDAR Activity
2.4. NMDARs Modulators
Compounds | Modulator | Selectivity | Action | References |
---|---|---|---|---|
D-AP5 | Competitive antagonist | GluN2A | Inhibits excitatory response. Impacts behavioral learning; blocks plasticity (LTP). | [95,96,97] |
Riluzole | Competitive antagonist | GluN1/GluN2B | Indirect block of NMDAR. Protects from motor deficit. | [103,104,105] |
Phencyclidine | Selective uncompetitive antagonist | GluN2B/D(PCP site) | Induces psychotic and dissociative schizophrenia-like symptoms. Impairs NMDAR neurotransmission in vivo. | [98] |
Ketamine | Uncompetitive antagonist | GluN2B/D(PCP site) | Applied in post-synapse: inhibits excitatory pyramidal neuron in extra-synaptic GluN2B. Applied in pre-synapse: inhibits GluN2D in interneuron (induces disinhibition of Glu release in post-synapse). Up-regulates hippocampal AMPARs (GluA1/GluA2). Antidepressant. | [100,106] |
Dizocilpine | Uncompetitive antagonist | GluN2A/B/D(PCP site) | Anticonvulsant, antidepressant. Induces memory impairments. | [102,107] |
Ifenprodil | Uncompetitive antagonist | GluN1/GluN2B(N-Terminal domain) | Blocks GluN2B (140-fold preference for NR2B over NR2A subunits). Induces inhibition of GluN2R receptor currents. Anti-Parkinsonian effect. | [108,109,110] |
Memantine | Uncompetitive antagonist | GluN1/GluN2B | Blocks GluN2B extra-synaptic and induces glutamatergic excitotoxicity. Used for moderate-to-severe AD. | [111,112] |
Amantadine | Uncompetitive antagonist | GluN1/GluN2B | Blocks GluN1/GluN2B by accelerating channel closure during channel block. Used as anti-Parkinsonian drug. | [113] |
Dextromethorphan | Uncompetitive antagonist | GluN2A | Blocks GluN2A subunit. Prevents neuronal damage and modulates pain sensation | [114,115,116,117,118] |
3. The Impact of NMDARs in Neurodegenerative Diseases
3.1. Alzheimer’s Disease
3.2. Huntington’s Disease
3.3. Parkinson’s Disease
4. Fluoroethylnormemantine (FENM): A New Generation NMDAR Uncompetitive Antagonist
4.1. 18F-FENM as a PET NMDAR Radiotracer
4.2. FENM as an Anxiolytic Agent in PTSD
4.3. FENM as a Neuroprotective Agent in AD
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ABD | agonist-binding domain |
AD | Alzheimer’s disease |
AMPAR | α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor |
Aβ | amyloid-β |
BDNF | brain-derived neurotrophic factor |
CaMKII | camodulin kinase II |
cAMP | 3′,5′-adenosine monophosphate |
cGMP | 3′,5′-guanosine monophosphate |
CNS | central nervous system |
CREB | cAMP response element-binding protein |
CTD | carboxyl C-terminal domain |
DYRK1A | dual-specificity tyrosine-phosphorylation-regulated kinase 1 |
EAAT | excitatory amino acid transporter |
ERK1/2 | extracellular signal-regulated protein kinase 1/2 |
FENM | fluoroethylnormemantine |
GABA | γ-aminobutyric acid |
HD | Huntington’s disease |
HEK-293 | human embryonic kidney 293 cells |
L-Dopa | L-3,4-dihydroxyphenylalanine |
LTD | long-term depression |
LTP | long-term potentiation |
MAPK | mitogen-activated protein kinases |
NMDAR | N-methyl-d-aspartate receptor |
PCP | phencycline |
PD | Parkinson’s disease |
PET | positron emission tomography |
PKA | protein kinase A |
PSD-95 | post-synaptic density protein 95 |
PTSD | post-traumatic stress disorder |
RCPG | G protein-coupled receptor |
SANT | sodium-coupled neutral amino acid transporter |
tPA | tissue-type plasminogen activator |
References
- Greenamyre, J.T.; Maragos, W.F.; Albin, R.L.; Penney, J.B.; Young, A.B. Glutamate transmission and toxicity in Alzheimer’s disease. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1988, 12, 421–430. [Google Scholar] [CrossRef] [PubMed]
- Reis, H.J.; Guatimosim, C.; Paquet, M.; Santos, M.; Ribeiro, F.M.; Kummer, A.; Schenatto, G.; Salgado, J.V.; Vieira, L.B.; Teixeira, A.L.; et al. Neuro-transmitters in the central nervous system & their implication in learning and memory processes. Curr. Med. Chem. 2009, 16, 796–840. [Google Scholar] [CrossRef] [PubMed]
- Dingledine, R.; Borges, K.; Bowie, D.; Traynelis, S.F. The glutamate receptor ion channels. Pharmacol. Rev. 1999, 51, 7–61. [Google Scholar]
- Volianskis, A.; France, G.; Jensen, M.S.; Bortolotto, Z.A.; Jane, D.E.; Collingridge, G.L. Long-term potentiation and the role of N-methyl-d-aspartate receptors. Brain Res. 2015, 1621, 5–16. [Google Scholar] [CrossRef] [PubMed]
- Lynch, G.; Baudry, M. The biochemistry of memory: A new and specific hypothesis. Science 1984, 8, 1057–1063. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; Peng, R.-Y. Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity. Mil. Med. Res. 2016, 3, 26. [Google Scholar] [CrossRef] [PubMed]
- Hardingham, G.E. NMDA receptor C-terminal signaling in development, plasticity, and disease. F1000Research 2019, 8, 1547. [Google Scholar] [CrossRef]
- Pol, A.N.V.D.; Hermans-Borgmeyer, I.; Hofer, M.; Ghosh, P.; Heinemann, S. Ionotropic glutamate-receptor gene expression in hypothalamus: Localization of AMPA, kainate, and NMDA receptor RNA with in situ hybridization. J. Comp. Neurol. 1994, 343, 428–444. [Google Scholar] [CrossRef] [PubMed]
- Tovar, K.R.; Westbrook, G.L. The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J. Neurosci. 1999, 19, 4180–4188. [Google Scholar] [CrossRef] [PubMed]
- Cottrell, J.R.; Dubé, G.R.; Egles, C.; Liu, G. Distribution, density, and clustering of functional glutamate receptors before and after synaptogenesis in hippocampal neurons. J. Neurophysiol. 2000, 84, 1573–1587. [Google Scholar] [CrossRef] [PubMed]
- Rodenas-Ruano, A.; Chávez, A.E.; Cossio, M.J.; Castillo, P.E.; Zukin, R.S. REST-dependent epigenetic remodeling promotes the in vivo developmental switch in NMDA receptors. Nat. Neurosci. 2012, 15, 1382–1390. [Google Scholar] [CrossRef] [PubMed]
- Hamada, S.; Ogawa, I.; Yamasaki, M.; Kiyama, Y.; Kassai, H.; Watabe, A.M.; Nakao, K.; Aiba, A.; Watanabe, M.; Manabe, T. The glutamate receptor GluN2 subunit regulates synaptic trafficking of AMPA receptors in the neonatal mouse brain. Eur. J. Neurosci. 2014, 40, 3136–3146. [Google Scholar] [CrossRef] [PubMed]
- Mayer, M.L.; Westbrook, G.L.; Guthrie, P.B. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 1984, 309, 261–263. [Google Scholar] [CrossRef] [PubMed]
- Hansen, K.B.; Yi, F.; Perszyk, R.E.; Furukawa, H.; Wollmuth, L.P.; Gibb, A.J.; Traynelis, S.F. Structure, function, and allosteric modulation of NMDA receptors. J. Gen. Physiol. 2018, 150, 1081–1105. [Google Scholar] [CrossRef] [PubMed]
- Nowak, L.; Bregestovski, P.; Ascher, P.; Herbet, A.; Prochiantz, A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 1984, 307, 462–465. [Google Scholar] [CrossRef] [PubMed]
- Johnson, J.W.; Ascher, P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 1987, 325, 529–531. [Google Scholar] [CrossRef] [PubMed]
- Kobayashi, K.; Manabe, T.; Takahashi, T. Presynaptic long-term depression at the hippocampal mossy fiber-CA3 synapse. Science 1996, 273, 648–650. [Google Scholar] [CrossRef] [PubMed]
- Malenka, R.C.; Kauer, J.A.; Perkel, D.J.; Nicoll, R.A. The impact of postsynaptic calcium on synaptic transmission—Its role in long-term potentiation. Trends Neurosci. 1989, 12, 444–450. [Google Scholar] [CrossRef] [PubMed]
- Zhou, Y.; Wang, X.; Tzingounis, A.; Danbolt, N.C.; Larsson, H.P. EAAT2 (GLT-1; slc1a2) glutamate transporters reconstituted in liposomes argues against heteroexchange being substantially faster than net uptake. J. Neurosci. 2014, 34, 13472–13485. [Google Scholar] [CrossRef]
- Dupuis, J.P.; Nicole, O.; Groc, L. NMDA receptor functions in health and disease: Old actor, new dimensions. Neuron 2023, 111, 2312–2328. [Google Scholar] [CrossRef]
- Geddes, J.W.; Cotman, C.W. Plasticity in hippocampal excitatory amino acid receptors in Alzheimer’s disease. Neurosci. Res. 1986, 3, 672–678. [Google Scholar] [CrossRef]
- Weiss, J.; Goldberg, M.P.; Choi, D.W. Ketamine protects cultured neocortical neurons from hypoxic injury. Brain Res. 1986, 380, 186–190. [Google Scholar] [CrossRef] [PubMed]
- Etienne, P.; Baudry, M. Calcium dependent aspects of synaptic plasticity, excitatory amino acid neurotransmission, brain aging and schizophrenia: A unifying hypothesis. Neurobiol. Aging 1987, 8, 362–366. [Google Scholar] [CrossRef] [PubMed]
- Adamec, R. Transmitter systems involved in neural plasticity underlying increased anxiety and defense-implications for understanding anxiety following traumatic stress. Neurosci. Biobehav. Rev. 1997, 21, 755–765. [Google Scholar] [CrossRef] [PubMed]
- Zeevalk, G.D.; Nicklas, W.J. Evidence that the loss of the voltage-dependent Mg2+ block at the N-methyl-d-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism. J. Neurochem. 1992, 59, 1211–1220. [Google Scholar] [CrossRef] [PubMed]
- Paoletti, P.; Bellone, C.; Zhou, Q. NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 2013, 14, 383–400. [Google Scholar] [CrossRef] [PubMed]
- Xia, P.; Chen, H.S.; Zhang, D.; Lipton, S.A. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J. Neurosci. 2010, 30, 11246–11250. [Google Scholar] [CrossRef]
- Stroebel, D.; Casado, M.; Paoletti, P. Triheteromeric NMDA receptors: From structure to synaptic physiology. Curr. Opin. Physiol. 2018, 2, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Traynelis, S.F.; Wollmuth, L.P.; McBain, C.J.; Menniti, F.S.; Vance, K.M.; Ogden, K.K.; Hansen, K.B.; Yuan, H.; Myers, S.J.; Dingledine, R. glutamate receptor ion channels: Structure, regulation, and function. Pharmacol. Rev. 2010, 62, 405–496. [Google Scholar] [CrossRef] [PubMed]
- Snell, L.D.; Johnson, K.M. Characterization of the inhibition of excitatory amino acid-induced neurotransmitter release in the rat striatum by phencyclidine-like drugs. J. Pharmacol. Exp. Ther. 1986, 238, 938–946. [Google Scholar] [PubMed]
- Burnashev, N.; Schoepfer, R.; Monyer, H.; Ruppersberg, J.P.; Günther, W.; Seeburg, P.H.; Sakmann, B. Control by asparagine residues of calcium permeability and magnesium blockade in the NMDA receptor. Science 1992, 257, 1415–1419. [Google Scholar] [CrossRef]
- Lee, E.; Williams, Z.; Goodman, C.B.; Oriaku, E.T.; Harris, C.; Thomas, M.; Soliman, K.F.A. Effects of NMDA receptor inhibition by phencyclidine on the neuronal differentiation of PC12 cells. Neurotoxicology 2006, 27, 558–566. [Google Scholar] [CrossRef]
- Paoletti, P.; Ascher, P.; Neyton, J. High-affinity zinc inhibition of NMDA NR1-NR2A receptors. J. Neurosci. 1997, 17, 5711–5725. [Google Scholar] [CrossRef] [PubMed]
- Sheng, M.; Cummings, J.; Roldan, L.A.; Jan, Y.N.; Jan, L.Y. Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature 1994, 368, 144–147. [Google Scholar] [CrossRef] [PubMed]
- Chazot, P.L.; Stephenson, F.A. Molecular dissection of native mammalian forebrain NMDA receptors containing the NR1 C2 exon: Direct demonstration of NMDA receptors comprising NR1, NR2A, and NR2B subunits within the same complex. J. Neurochem. 1997, 69, 2138–2144. [Google Scholar] [CrossRef] [PubMed]
- Luo, J.; Wang, Y.; Yasuda, R.P.; Dunah, A.W.; Wolfe, B.B. The majority of N-methyl-d-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR1/NR2A/NR2B). Mol. Pharmacol. 1997, 51, 79–86. [Google Scholar] [CrossRef] [PubMed]
- Al-Hallaq, R.A.; Conrads, T.P.; Veenstra, T.D.; Wenthold, R.J. NMDA di-heteromeric receptor populations and associated proteins in rat hippocampus. J. Neurosci. 2007, 27, 8334–8343. [Google Scholar] [CrossRef] [PubMed]
- Monyer, H.; Sprengel, R.; Schoepfer, R.; Herb, A.; Higuchi, M.; Lomeli, H.; Burnashev, N.; Sakmann, B.; Seeburg, P.H. Heteromeric NMDA receptors: Molecular and functional distinction of subtypes. Science 1992, 256, 1217–1221. [Google Scholar] [CrossRef] [PubMed]
- Pérez-Otaño, I.; Luján, R.; Tavalin, S.J.; Plomann, M.; Modregger, J.; Liu, X.-B.; Jones, E.G.; Heinemann, S.F.; Lo, D.C.; Ehlers, M.D. Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PAC-SIN1/syndapin1. Nat. Neurosci. 2006, 9, 611–621. [Google Scholar] [CrossRef] [PubMed]
- Zhong, W.; Wu, A.; Berglund, K.; Gu, X.; Jiang, M.Q.; Talati, J.; Zhao, J.; Wei, L.; Yu, S.P. Pathogenesis of sporadic Alzheimer’s disease by deficiency of NMDA receptor subunit GluN3A. Alzheimers Dement. 2022, 18, 222–239. [Google Scholar] [CrossRef] [PubMed]
- Grand, T.; Abi Gerges, S.; David, M.; Diana, M.A.; Paoletti, P. Unmasking GluN1/GluN3A excitatory glycine NMDA receptors. Nat. Commun. 2018, 9, 4769. [Google Scholar] [CrossRef]
- Harney, S.C.; Jane, D.E.; Anwyl, R. Extrasynaptic NR2D-containing NMDARs are recruited to the synapse during LTP of NMDAR-EPSCs. J. Neurosci. 2008, 28, 11685–11694. [Google Scholar] [CrossRef] [PubMed]
- Eapen, A.V.; Fernández-Fernández, D.; Georgiou, J.; Bortolotto, Z.A.; Lightman, S.; Jane, D.E.; Volianskis, A.; Collingridge, G.L. Multiple roles of GluN2D-containing NMDA receptors in short-term potentiation and long-term potentiation in mouse hippocampal slices. Neuropharmacology 2021, 201, 108833. [Google Scholar] [CrossRef] [PubMed]
- Halassa, M.M.; Fellin, T.; Haydon, P.G. The tripartite synapse: Roles for gliotransmission in health and disease. Trends Mol. Med. 2007, 13, 54–63. [Google Scholar] [CrossRef]
- Yoshioka, A.; Yamaya, Y.; Saiki, S.; Kanemoto, M.; Hirose, G.; Beesley, J.; Pleasure, D. Non-N-methyl-d-aspartate glutamate receptors mediate oxygen-glucose deprivation-induced oligodendroglial injury. Brain Res. 2000, 854, 207–215. [Google Scholar] [CrossRef]
- Saab, A.S.; Tzvetavona, I.D.; Trevisiol, A.; Baltan, S.; Dibaj, P.; Kusch, K.; Möbius, W.; Goetze, B.; Jahn, H.M.; Huang, W.; et al. Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 2016, 91, 119–132. [Google Scholar] [CrossRef]
- Palygin, O.; Lalo, U.; Pankratov, Y. Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes. Br. J. Pharmacol. 2011, 163, 1755–1766. [Google Scholar] [CrossRef] [PubMed]
- Adamsky, A.; Kol, A.; Kreisel, T.; Doron, A.; Ozeri-Engelhard, N.; Melcer, T.; Refaeli, R.; Horn, H.; Regev, L.; Groysman, M.; et al. Astrocytic activation generates de novo neuronal potentiation and memory enhancement. Cell 2018, 174, 59–71.e14. [Google Scholar] [CrossRef] [PubMed]
- Perea, G.; Araque, A. Astrocytes potentiate transmitter release at single hippocampal synapses. Science 2007, 317, 1083–1086. [Google Scholar] [CrossRef] [PubMed]
- Henneberger, C.; Papouin, T.; Oliet, S.H.R.; Rusakov, D.A. Long-term potentiation depends on release of D-serine from as-trocytes. Nature 2010, 463, 232–236. [Google Scholar] [CrossRef] [PubMed]
- Lalo, U.; Koh, W.; Lee, C.J.; Pankratov, Y. The tripartite glutamatergic synapse. Neuropharmacology 2021, 199, 108758. [Google Scholar] [CrossRef] [PubMed]
- Raghunatha, P.; Vosoughi, A.; Kauppinen, T.M.; Jackson, M.F. Microglial NMDA receptors drive pro-inflammatory responses via PARP-1/TRMP2 signaling. Glia 2020, 68, 1421–1434. [Google Scholar] [CrossRef] [PubMed]
- Clements, J.D.; Lester, R.A.; Tong, G.; Jahr, C.E.; Westbrook, G.L. The time course of glutamate in the synaptic cleft. Science 1992, 258, 1498–1501. [Google Scholar] [CrossRef] [PubMed]
- Grewal, S.; Defamie, N.; Zhang, X.; De Gois, S.; Shawki, A.; Mackenzie, B.; Chen, C.; Varoqui, H.; Erickson, J.D. SNAT2 amino acid transporter is regulated by amino acids of the SLC6 gamma-aminobutyric acid transporter subfamily in neocortical neurons and may play no role in delivering glutamine for glutamatergic transmission. J. Biol. Chem. 2009, 284, 11224–11236. [Google Scholar] [CrossRef]
- Lüscher, C.; Malenka, R.C. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb. Perspect. Biol. 2012, 4, a005710. [Google Scholar] [CrossRef] [PubMed]
- Zhou, X.; Zheng, F.; Moon, C.; Schlüter, O.M.; Wang, H. Bi-directional regulation of CaMKIIα phosphorylation at Thr286 by NMDA receptors in cultured cortical neurons. J. Neurochem. 2012, 122, 295–307. [Google Scholar] [CrossRef]
- Kristensen, A.S.; Jenkins, M.A.; Banke, T.G.; Schousboe, A.; Makino, Y.; Johnson, R.C.; Huganir, R.; Traynelis, S.F. Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating. Nat. Neurosci. 2011, 14, 727–735. [Google Scholar] [CrossRef]
- Yang, X.; Gong, R.; Qin, L.; Bao, Y.; Fu, Y.; Gao, S.; Yang, H.; Ni, J.; Yuan, T.-F.; Lu, W. Trafficking of NMDA receptors is es-sential for hippocampal synaptic plasticity and memory consolidation. Cell Rep. 2022, 40, 111217. [Google Scholar] [CrossRef]
- Niethammer, M.; Kim, E.; Sheng, M. Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases. J. Neurosci. 1996, 16, 2157–2163. [Google Scholar] [CrossRef]
- El-Husseini, A.E.; Schnell, E.; Chetkovich, D.M.; Nicoll, R.A.; Bredt, D.S. PSD-95 involvement in maturation of excitatory synapses. Science 2000, 290, 1364–1368. [Google Scholar] [CrossRef] [PubMed]
- Lim, I.A.; Hall, D.D.; Hell, J.W. Selectivity and promiscuity of the first and second PDZ domains of PSD-95 and synapse-associated protein 102. J. Biol. Chem. 2002, 277, 21697–21711. [Google Scholar] [CrossRef]
- Barco, A.; Alarcon, J.M.; Kandel, E.R. Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 2002, 108, 689–703. [Google Scholar] [CrossRef] [PubMed]
- Benito, E.; Barco, A. CREB’s control of intrinsic and synaptic plasticity: Implications for CREB-dependent memory models. Trends Neurosci. 2010, 33, 230–240. [Google Scholar] [CrossRef] [PubMed]
- Fiumelli, H.; Jabaudon, D.; Magistretti, P.J.; Martin, J.L. BDNF stimulates expression, activity and release of tissue-type plasminogen activator in mouse cortical neurons. Eur. J. Neurosci. 1999, 11, 1639–1646. [Google Scholar] [CrossRef] [PubMed]
- Pang, P.T.; Teng, H.K.; Zaitsev, E.; Woo, N.T.; Sakata, K.; Zhen, S.; Teng, K.K.; Yung, W.H.; Hempstead, B.L.; Lu, B. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 2004, 306, 487–491. [Google Scholar] [CrossRef]
- Mulkey, R.M.; Herron, C.E.; Malenka, R.C. An essential role for protein phosphatases in hippocampal long-term depression. Science 1993, 261, 1051–1055. [Google Scholar] [CrossRef]
- Li, Z.; Jo, J.; Jia, J.-M.; Lo, S.-C.; Whitcomb, D.J.; Jiao, S.; Cho, K.; Sheng, M. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 2010, 141, 859–871. [Google Scholar] [CrossRef]
- Bloodgood, B.L.; Giessel, A.J.; Sabatini, B.L. Biphasic synaptic Ca influx arising from compartmentalized elec-trical signals in dendritic spines. PLoS Biol. 2009, 7, e1000190. [Google Scholar] [CrossRef] [PubMed]
- Lanté, F.; Cavalier, M.; Cohen-Solal, C.; Guiramand, J.; Vignes, M. Developmental switch from LTD to LTP in low frequency-induced plasticity. Hippocampus 2006, 16, 981–989. [Google Scholar] [CrossRef] [PubMed]
- Roche, K.W.; Standley, S.; McCallum, J.; Dune Ly, C.; Ehlers, M.D.; Wenthold, R.J. Molecular determinants of NMDA recep-tor internalization. Nat. Neurosci. 2001, 4, 794–802. [Google Scholar] [CrossRef] [PubMed]
- Grosshans, D.R.; Clayton, D.A.; Coultrap, S.J.; Browning, M.D. LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult rat CA1. Nat. Neurosci. 2002, 5, 27–33. [Google Scholar] [CrossRef] [PubMed]
- Yashiro, K.; Philpot, B.D. Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and meta-plasticity. Neuropharmacology 2008, 55, 1081–1094. [Google Scholar] [CrossRef] [PubMed]
- Liu, L.; Wong, T.P.; Pozza, M.F.; Lingenhoehl, K.; Wang, Y.; Sheng, M.; Auberson, Y.P.; Wang, Y.T. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 2004, 304, 1021–1024. [Google Scholar] [CrossRef] [PubMed]
- Bellone, C.; Nicoll, R.A. Rapid bidirectional switching of synaptic NMDA receptors. Neuron 2007, 55, 779–785. [Google Scholar] [CrossRef] [PubMed]
- Dupuis, J.P.; Ladépêche, L.; Seth, H.; Bard, L.; Varela, J.; Mikasova, L.; Bouchet, D.; Rogemond, V.; Honnorat, J.; Hanse, E.; et al. Surface dynamics of GluN2B-NMDA receptors controls plasticity of maturing glutamate synapses. EMBO J. 2014, 33, 842–861. [Google Scholar] [CrossRef] [PubMed]
- Sanz-Clemente, A.; Matta, J.A.; Isaac, J.T.R.; Roche, K.W. Casein kinase 2 regulates the NR2 subunit composition of synaptic NMDA receptors. Neuron 2010, 67, 984–996. [Google Scholar] [CrossRef] [PubMed]
- Sanz-Clemente, A.; Gray, J.A.; Ogilvie, K.A.; Nicoll, R.A.; Roche, K.W. Activated CaMKII couples GluN2B and casein kinase 2 to control synaptic NMDA receptors. Cell Rep. 2013, 3, 607–614. [Google Scholar] [CrossRef] [PubMed]
- Borgdorff, A.J.; Choquet, D. Regulation of AMPA receptor lateral movements. Nature 2002, 417, 649–653. [Google Scholar] [CrossRef] [PubMed]
- Opazo, P.; Labrecque, S.; Tigaret, C.M.; Frouin, A.; Wiseman, P.W.; De Koninck, P.; Choquet, D. CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron 2010, 67, 239–252. [Google Scholar] [CrossRef] [PubMed]
- Sumioka, A.; Yan, D.; Tomita, S. TARP phosphorylation regulates synaptic AMPA receptors through lipid bilayers. Neuron 2010, 66, 755–767. [Google Scholar] [CrossRef]
- Penn, A.C.; Zhang, C.L.; Georges, F.; Royer, L.; Breillat, C.; Hosy, E.; Petersen, J.D.; Humeau, Y.; Choquet, D. Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors. Nature 2017, 549, 384–388. [Google Scholar] [CrossRef] [PubMed]
- Gardoni, F.; Schrama, L.H.; Kamal, A.; Gispen, W.H.; Cattabeni, F.; Di Luca, M. Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor. J. Neurosci. 2001, 21, 1501–1509. [Google Scholar] [CrossRef] [PubMed]
- Gardoni, F.; Mauceri, D.; Fiorentini, C.; Bellone, C.; Missale, C.; Cattabeni, F.; Di Luca, M. CaMKII-dependent phosphoryla-tion regulates SAP97/NR2A interaction. J. Biol. Chem. 2003, 278, 44745–44752. [Google Scholar] [CrossRef]
- Mauceri, D.; Gardoni, F.; Marcello, E.; Di Luca, M. Dual role of CaMKII-dependent SAP97 phosphorylation in mediating trafficking and insertion of NMDA receptor subunit NR2A. J. Neurochem. 2007, 100, 1032–1046. [Google Scholar] [CrossRef] [PubMed]
- Tingley, W.G.; Ehlers, M.D.; Kameyama, K.; Doherty, C.; Ptak, J.B.; Riley, C.T.; Huganir, R.L. Characterization of protein kinase A and protein kinase C phosphorylation of the N-methyl-d-aspartate receptor NR1 subunit using phosphorylation site-specific antibodies. J. Biol. Chem. 1997, 272, 5157–5166. [Google Scholar] [CrossRef] [PubMed]
- Scott, D.B.; Blanpied, T.A.; Swanson, G.T.; Zhang, C.; Ehlers, M.D. An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing. J. Neurosci. 2001, 21, 3063–3072. [Google Scholar] [CrossRef] [PubMed]
- Scott, D.B.; Blanpied, T.A.; Ehlers, M.D. Coordinated PKA and PKC phosphorylation suppresses RXR-mediated ER reten-tion and regulates the surface delivery of NMDA receptors. Neuropharmacology 2003, 45, 755–767. [Google Scholar] [CrossRef]
- Taniguchi, S.; Nakazawa, T.; Tanimura, A.; Kiyama, Y.; Tezuka, T.; Watabe, A.M.; Katayama, N.; Yokoyama, K.; Inoue, T.; Izumi-Nakaseko, H.; et al. Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour. EMBO J. 2009, 28, 3717–3729. [Google Scholar] [CrossRef]
- Grau, C.; Arató, K.; Fernández-Fernández, J.M.; Valderrama, A.; Sindreu, C.; Fillat, C.; Ferrer, I.; de la Luna, S.; Altafaj, X. DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors. Front. Cell Neurosci. 2014, 8, 331. [Google Scholar] [CrossRef] [PubMed]
- Lee, C.-C.; Chang, C.-P.; Lin, C.-J.; Lai, H.-L.; Kao, Y.-H.; Cheng, S.-J.; Chen, H.-M.; Liao, Y.-P.; Faivre, E.; Buée, L.; et al. Adenosine augmentation evoked by an ENT1 inhibitor improves memory impairment and neuronal plasticity in the APP/PS1 mouse model of Alzheimer’s disease. Mol. Neurobiol. 2018, 55, 8936–8952. [Google Scholar] [CrossRef] [PubMed]
- Nakazawa, T.; Komai, S.; Tezuka, T.; Hisatsune, C.; Umemori, H.; Semba, K.; Mishina, M.; Manabe, T.; Yamamoto, T. Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-d-aspartate receptor. J. Biol. Chem. 2001, 276, 693–699. [Google Scholar] [CrossRef] [PubMed]
- Snyder, E.M.; Nong, Y.; Almeida, C.G.; Paul, S.; Moran, T.; Choi, E.Y.; Nairn, A.C.; Salter, M.W.; Lombroso, P.J.; Gouras, G.K.; et al. Regulation of NMDA receptor trafficking by amyloid-β. Nat. Neurosci. 2005, 8, 1051–1058. [Google Scholar] [CrossRef] [PubMed]
- Chen, T.; Zhang, B.; Li, G.; Chen, L.; Chen, L. Simvastatin enhances NMDA receptor GluN2B expression and phosphorylation of GluN2B and GluN2A through increased histone acetylation and Src signaling in hippocampal CA1 neurons. Neuropharmacology 2016, 107, 411–421. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Meng, Z.-X.; Chen, Y.-Z.; Li, Y.-P.; Zhou, H.-Y.; Yang, M.; Zhao, T.-T.; Gong, Y.-L.; Wu, Y.; Liu, T. Enriched environ-ment enhances histone acetylation of NMDA receptor in the hippocampus and improves cognitive dysfunction in aged mice. Neural Regen. Res. 2020, 15, 2327–2334. [Google Scholar] [CrossRef] [PubMed]
- Morris, R.G.; Anderson, E.; Lynch, G.S.; Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-d-aspartate receptor antagonist, AP5. Nature 1986, 319, 774–776. [Google Scholar] [CrossRef] [PubMed]
- Davis, S.; Butcher, S.P.; Morris, R.G. The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J. Neurosci. 1992, 12, 21–34. [Google Scholar] [CrossRef]
- Lodge, D.; Watkins, J.C.; Bortolotto, Z.A.; Jane, D.E.; Volianskis, A. The 1980s: D-AP5, LTP and a decade of NMDA receptor discoveries. Neurochem. Res. 2019, 44, 516–530. [Google Scholar] [CrossRef] [PubMed]
- Gozzi, A.; Herdon, H.; Schwarz, A.; Bertani, S.; Crestan, V.; Turrini, G.; Bifone, A. Pharmacological stimulation of NMDA receptors via co-agonist site suppresses fMRI response to phencyclidine in the rat. Psychopharmacology 2008, 201, 273–284. [Google Scholar] [CrossRef] [PubMed]
- Li, J.-H.; Vicknasingam, B.; Cheung, Y.-W.; Zhou, W.; Nurhidayat, A.W.; Jarlais, D.C.D.; Schottenfeld, R. To use or not to use: An update on licit and illicit ketamine use. Subst. Abus. Rehabil. 2011, 2, 11–20. [Google Scholar] [CrossRef]
- Pothula, S.; Kato, T.; Liu, R.-J.; Wu, M.; Gerhard, D.; Shinohara, R.; Sliby, A.-N.; Chowdhury, G.M.I.; Behar, K.L.; Sanacora, G.; et al. Cell-type specific modulation of NMDA receptors triggers antidepressant actions. Mol. Psychiatr. 2021, 26, 5097–5111. [Google Scholar] [CrossRef] [PubMed]
- Zanos, P.; Brown, K.A.; Georgiou, P.; Yuan, P.; Zarate, C.A.; Thompson, S.M.; Gould, T.D. NMDA receptor activation-dependent antidepressant-relevant behavioral and synaptic actions of ketamine. J. Neurosci. 2023, 43, 1038–1050. [Google Scholar] [CrossRef] [PubMed]
- Maurice, T.; Su, T.P.; Parish, D.W.; Nabeshima, T.; Privat, A. PRE-084, a sigma selective PCP derivative, attenuates MK-801-induced impairment of learning in mice. Pharmacol. Biochem. Behav. 1994, 49, 859–869. [Google Scholar] [CrossRef] [PubMed]
- Hubert, J.P.; Delumeau, J.C.; Glowinski, J.; Prémont, J.; Doble, A. Antagonism by riluzole of entry of calcium evoked by NMDA and veratridine in rat cultured granule cells: Evidence for a dual mechanism of action. Br. J. Pharmacol. 1994, 113, 261–267. [Google Scholar] [CrossRef] [PubMed]
- Kretschmer, B.D.; Kratzer, U.; Schmidt, W.J. Riluzole, a glutamate release inhibitor, and motor behavior. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1998, 358, 181–190. [Google Scholar] [CrossRef] [PubMed]
- Lamanauskas, N.; Nistri, A. Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via pre-synaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur. J. Neurosci. 2008, 27, 2501–2514. [Google Scholar] [CrossRef] [PubMed]
- Berman, R.M.; Cappiello, A.; Anand, A.; Oren, D.A.; Heninger, G.R.; Charney, D.S.; Krystal, J.H. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 2000, 47, 351–354. [Google Scholar] [CrossRef] [PubMed]
- Sircar, R.; Rappaport, M.; Nichtenhauser, R.; Zukin, S.R. The novel anticonvulsant MK-801: A potent and specific ligand of the brain phencyclidine/sigma-receptor. Brain Res. 1987, 435, 235–240. [Google Scholar] [CrossRef] [PubMed]
- Mitchell, I.J.; Hughes, N.; Carroll, C.B.; Brotchie, J.M. Reversal of parkinsonian symptoms by intrastriatal and systemic manipulations of excitatory amino acid and dopamine transmission in the bilateral 6-OHDA lesioned marmoset. Behav. Pharmacol. 1995, 6, 492–507. [Google Scholar] [CrossRef]
- Gallagher, M.J.; Huang, H.; Pritchett, D.B.; Lynch, D.R. Interactions between ifenprodil and the NR2B subunit of the N-Methyl-d-aspartate receptor. J. Biol. Chem. 1996, 271, 9603–9611. [Google Scholar] [CrossRef]
- Sarre, S.; Lanza, M.; Makovec, F.; Artusi, R.; Caselli, G.; Michotte, Y. In vivo neurochemical effects of the NR2B selective NMDA receptor antagonist CR 3394 in 6-hydroxydopamine lesioned rats. Eur. J. Pharmacol. 2008, 584, 297–305. [Google Scholar] [CrossRef] [PubMed]
- Danysz, W.; Parsons, C.G. The NMDA receptor antagonist memantine as a symptomatological and neuro-protective treatment for Alzheimer’s disease: Preclinical evidence. Int. J. Geriatr. Psychiatry 2003, 18, S23–S32. [Google Scholar] [CrossRef] [PubMed]
- Murakawa-Hirachi, T.; Mizoguchi, Y.; Ohgidani, M.; Haraguchi, Y.; Monji, A. Effect of memantine, an anti-Alzheimer’s drug, on rodent microglial cells in vitro. Sci. Rep. 2021, 11, 6151. [Google Scholar] [CrossRef] [PubMed]
- Blanpied, T.A.; Clarke, R.J.; Johnson, J.W. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J. Neurosci. 2005, 25, 3312–3322. [Google Scholar] [CrossRef]
- Block, F.; Schwarz, M. Dextromethorphan reduces functional deficits and neuronal damage after global ischemia in rats. Brain Res. 1996, 741, 153–159. [Google Scholar] [CrossRef] [PubMed]
- Dere, E.; Topic, B.; De Souza Silva, M.A.; Fink, H.; Buddenberg, T.; Huston, J.P. NMDA-receptor antagonism via dextromethorphan and ifenprodil modulates graded anxiety test performance of C57BL/6 mice. Behav. Pharmacol. 2003, 14, 245–249. [Google Scholar] [CrossRef] [PubMed]
- Kemppainen, P.; Waltimo, A.; Waltimo, T.; Könönen, M.; Pertovaara, A. Differential effects of noxious conditioning stimulation of the cheek by capsaicin on human sensory and inhibitory masseter reflex responses evoked by tooth pulp stimulation. J. Dent. Res. 1997, 76, 1561–1568. [Google Scholar] [CrossRef] [PubMed]
- Weinbroum, A.A.; Gorodetzky, A.; Nirkin, A.; Kollender, Y.; Bickels, J.; Marouani, N.; Rudick, V.; Meller, I. Dextrome-thorphan for the reduction of immediate and late postoperative pain and morphine consumption in orthopedic oncology patients: A randomized, placebo-controlled, double-blind study. Cancer 2002, 95, 1164–1170. [Google Scholar] [CrossRef]
- Weinbroum, A.A.; Bender, B.; Nirkin, A.; Chazan, S.; Meller, I.; Kollender, Y. Dextromethorphan-associated epidural patient-controlled analgesia provides better pain- and analgesics-sparing effects than dextromethorphan-associated intravenous patient-controlled analgesia after bone-malignancy resection: A randomized, placebo-controlled, double-blinded study. Anesth. Analg. 2004, 98, 714–722. [Google Scholar] [CrossRef] [PubMed]
- Williams, K. Ifenprodil discriminates subtypes of the N-methyl-d-aspartate receptor: Selectivity and mechanisms at recombinant heteromeric receptors. Mol. Pharmacol. 1993, 44, 851–859. [Google Scholar] [PubMed]
- Tajima, N.; Karakas, E.; Grant, T.; Simorowski, N.; Diaz-Avalos, R.; Grigorieff, N.; Furukawa, H. Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature 2016, 534, 63–68. [Google Scholar] [CrossRef] [PubMed]
- Matsunaga, S.; Kishi, T.; Nomura, I.; Sakuma, K.; Okuya, M.; Ikuta, T.; Iwata, N. The efficacy and safety of memantine for the treatment of Alzheimer’s disease. Exp. Opin. Drug Saf. 2018, 17, 1053–1061. [Google Scholar] [CrossRef] [PubMed]
- Schwartz, A.R.; Pizon, A.F.; Brooks, D.E. Dextromethorphan-induced serotonin syndrome. Clin. Toxicol. 2008, 46, 771–773. [Google Scholar] [CrossRef] [PubMed]
- Guyot, M.C.; Hantraye, P.; Dolan, R.; Palfi, S.; Maziére, M.; Brouillet, E. Quantifiable bradykinesia, gait abnormalities and Huntington’s disease-like striatal lesions in rats chronically treated with 3-nitropropionic acid. Neuroscience 1997, 79, 45–56. [Google Scholar] [CrossRef]
- Albin, R.L.; Greenamyre, J.T. Alternative excitotoxic hypotheses. Neurology 1992, 42, 733–738. [Google Scholar] [CrossRef] [PubMed]
- Ingelsson, M.; Fukumoto, H.; Newell, K.L.; Growdon, J.H.; Hedley-Whyte, E.T.; Frosch, M.P.; Albert, M.S.; Hyman, B.T.; Irizarry, M.C. Early Ab accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 2004, 62, 925–931. [Google Scholar] [CrossRef] [PubMed]
- Scheff, S.W.; Price, D.A.; Schmitt, F.A.; Mufson, E.J. Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol. Aging 2006, 27, 1372–1384. [Google Scholar] [CrossRef]
- Fonte, C.; Smania, N.; Pedrinolla, A.; Munari, D.; Gandolfi, M.; Picelli, A.; Varalta, V.; Benetti, M.V.; Brugnera, A.; Federico, A.; et al. Comparison between physical and cognitive treatment in patients with MIC and Alzheimer’s disease. Aging 2019, 11, 3138–3155. [Google Scholar] [CrossRef] [PubMed]
- Blinkouskaya, Y.; Weickenmeier, J. Brain shape changes associated with cerebral atrophy in healthy aging and Alzheimer’s disease. Front. Mech. Eng. 2021, 7, 705653. [Google Scholar] [CrossRef] [PubMed]
- Shankar, G.M.; Bloodgood, B.L.; Townsend, M.; Walsh, D.M.; Selkoe, D.J.; Sabatini, B.L. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 2007, 27, 2866–2875. [Google Scholar] [CrossRef] [PubMed]
- Lei, M.; Xu, H.; Li, Z.; Wang, Z.; O’Malley, T.T.; Zhang, D.; Walsh, D.M.; Xu, P.; Selkoe, D.J.; Li, S. Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance. Neurobiol. Dis. 2016, 85, 111–121. [Google Scholar] [CrossRef] [PubMed]
- Simpson, J.E.; Ince, P.G.; Lace, G.; Forster, G.; Shaw, P.J.; Matthews, F.; Savva, G.; Brayne, C.; Wharton, S.B. Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol. Aging 2010, 31, 578–590. [Google Scholar] [CrossRef] [PubMed]
- Wei, W.; Nguyen, L.N.; Kessels, H.W.; Hagiwara, H.; Sisodia, S.; Malinow, R. Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat. Neurosci. 2010, 13, 190–196. [Google Scholar] [CrossRef] [PubMed]
- Li, S.; Jin, M.; Koeglsperger, T.; Shepardson, N.E.; Shankar, G.M.; Selkoe, D.J. Soluble Aβ oligomers inhibit long-term poten-tiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J. Neurosci. 2011, 31, 6627–6638. [Google Scholar] [CrossRef]
- Companys-Alemany, J.; Turcu, A.L.; Vázquez, S.; Pallàs, M.; Griñán-Ferré, C. Glial cell reactivity and oxidative stress prevention in Alzheimer’s disease mice model by an optimized NMDA receptor antagonist. Sci. Rep. 2022, 12, 17908. [Google Scholar] [CrossRef] [PubMed]
- Esposito, Z.; Belli, L.; Toniolo, S.; Sancesario, G.; Bianconi, C.; Martorana, A. Amyloid β, Glutamate, Excitotoxicity in Alzheimer’s Disease: Are We on the Right Track? CNS Neurosci. Ther. 2013, 19, 549–555. [Google Scholar] [CrossRef] [PubMed]
- Ittner, L.M.; Ke, Y.D.; Delerue, F.; Bi, M.; Gladbach, A.; van Eersel, J.; Wölfing, H.; Chieng, B.C.; Christie, M.J.; Napier, I.A.; et al. Dendritic function of tau mediates amyloid-b toxicity in Alzheimer’s disease mouse models. Cell 2010, 142, 387–397. [Google Scholar] [CrossRef] [PubMed]
- Vitolo, O.V.; Sant’Angelo, A.; Costanzo, V.; Battaglia, F.; Arancio, O.; Shelanski, M. Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling. Proc. Natl. Acad. Sci. USA 2002, 99, 13217–13221. [Google Scholar] [CrossRef] [PubMed]
- Rosa, E.; Fahnestock, M. CREB expression mediates amyloid β-induced basal BDNF downregulation. Neurobiol. Aging 2015, 36, 2406–2413. [Google Scholar] [CrossRef] [PubMed]
- Taylor, H.B.C.; Emptage, N.J.; Jeans, A.F. Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau. Cell Rep. 2021, 36, 109638. [Google Scholar] [CrossRef] [PubMed]
- Bordji, K.; Becerril-Ortega, J.; Nicole, O.; Buisson, A. Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ß production. J. Neurosci. 2010, 30, 15927–15942. [Google Scholar] [CrossRef] [PubMed]
- Sze, S.C.; Wong, C.K.; Yung, K.K. Modulation of the gene expression of N-methyl-d-aspartate receptor NR2B subunit in the rat neostriatum by a single dose of specific antisense oligodeoxynucleotide. Neurochem. Int. 2001, 39, 319–327. [Google Scholar] [CrossRef] [PubMed]
- Bi, H.; Sze, C.-I. N-Methyl-d-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippo-campus and entorhinal cortex in Alzheimer’s disease. J. Neurol. Sci. 2002, 200, 11–18. [Google Scholar] [CrossRef] [PubMed]
- Hynd, M.R.; Scott, H.L.; Dodd, P.R. Differential expression of N-methyl-d-aspartate receptor NR2 isoforms in Alzheimer’s disease. J. Neurochem. 2004, 90, 913–919. [Google Scholar] [CrossRef] [PubMed]
- Mishizen-Eberz, A.J.; Rissman, R.A.; Carter, T.L.; Ikonomovic, M.D.; Wolfe, B.B.; Armstrong, D.M. Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout progression of Alzheimer’s disease pathology. Neurobiol. Dis. 2004, 15, 80–92. [Google Scholar] [CrossRef] [PubMed]
- Tsang, S.W.Y.; Vinters, H.V.; Cummings, J.L.; Wong, P.T.-H.; Chen, C.P.L.-H.; Lai, M.K.P. Alterations in NMDA receptor subunit densities and ligand binding to glycine recognition sites are associated with chronic anxiety in Alzheimer’s disease. Neurobiol. Aging 2008, 29, 1524–1532. [Google Scholar] [CrossRef] [PubMed]
- Mielke, M.M.; Aggarwal, N.T.; Vila-Castelar, C.; Agarwal, P.; Arenaza-Urquijo, E.M.; Brett, B.; Brugulat-Serrat, A.; DuBose, L.E.; Eikelboom, W.S.; Flatt, J.; et al. Diversity and Disparity Professional Interest Area Sex and Gender Special Interest Group. Consideration of sex and gender in Alzheimer’s disease and related disorders from a global perspective. Alzheimers Dement. 2022, 18, 2707–2724. [Google Scholar] [CrossRef] [PubMed]
- Snyder, H.M.; Asthana, S.; Bain, L.; Brinton, R.; Craft, S.; Dubal, D.B.; Espeland, M.A.; Gatz, M.; Mielke, M.M.; Raber, J.; et al. Sex biology contributions to vulnerability to Alzheimer’s disease: A think tank convened by the women’s Alzheimer’s research initiative. Alzheimers Dement. 2016, 12, 1186–1196. [Google Scholar] [CrossRef] [PubMed]
- Maffioli, E.; Murtas, G.; Rabattoni, V.; Badone, B.; Tripodi, F.; Iannuzzi, F.; Licastro, D.; Nonnis, S.; Rinaldi, A.M.; Motta, Z.; et al. Insulin and serine metabolism as sex-specific hallmarks of Alzheimer’s disease in the human hippocampus. Cell Rep. 2022, 40, 111271. [Google Scholar] [CrossRef] [PubMed]
- Papouin, T.; Ladépêche, L.; Ruel, J.; Sacchi, S.; Labasque, M.; Hanini, M.; Groc, L.; Pollegioni, L.; Mothet, J.P.; Oliet, S.H. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 2012, 150, 633–646. [Google Scholar] [CrossRef] [PubMed]
- Baier, M.P.; Nagaraja, R.Y.; Yarbrough, H.P.; Owen, D.B.; Masingale, A.M.; Ranjit, R.; Stiles, M.A.; Murphy, A.; Agbaga, M.P.; Ahmad, M.; et al. Selective ablation of Sod2 in astrocytes induces sex-specific effects on cognitive function, d-serine availability, and astrogliosis. J. Neurosci. 2022, 42, 5992–6006. [Google Scholar] [CrossRef] [PubMed]
- Schmitt, F.A.; Ashford, W.; Ernesto, C.; Saxton, J.; Schneider, L.S.; Clark, C.M.; Ferris, S.H.; Mackell, J.A.; Schafer, K.; Thal, L.J. The severe impairment battery: Concurrent validity and the assessment of longitudinal change in Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis. Assoc. Disord. 1997, 11 (Suppl. 2), S51–S56. [Google Scholar]
- Tariot, P.N.; Farlow, M.R.; Grossberg, G.T.; Graham, S.M.; McDonald, S.; Gergel, I.; For the Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil. A randomized controlled trial. J. Am. Med. Assoc. 2004, 291, 317–324. [Google Scholar] [CrossRef] [PubMed]
- Mimica, N.; Presecki, P. Side effects of approved antidementives. Psychiatr. Danub. 2009, 21, 108–113. [Google Scholar] [PubMed]
- Medina, A.; Mahjoub, Y.; Shaver, L.; Pringsheim, T. Prevalence and incidence of Huntington’s disease: An updated systematic review and meta-analysis. Mov. Disord. 2022, 37, 2327–2335. [Google Scholar] [CrossRef] [PubMed]
- Reiner, A.; Albin, R.L.; Anderson, K.D.; D’Amato, C.J.; Penney, J.B.; Young, A.B. Differential loss of striatal projection neurons in Huntington disease. Proc. Natl. Acad. Sci. USA 1988, 85, 5733–5737. [Google Scholar] [CrossRef] [PubMed]
- Foroud, T.; Gray, J.; Ivashina, J.; Conneally, P.M. Differences in duration of Huntington’s disease based on age at onset. J. Neurol. Neurosurg. Psychiatr. 1999, 66, 52–56. [Google Scholar] [CrossRef] [PubMed]
- Dorsey, E.R.; Beck, C.A.; Darwin, K.; Nichols, P.; Brocht, A.F.D.; Biglan, K.M.; Shoulson, I.; Huntington Study Group CO-HORT Investigators. Natural history of Huntington disease. JAMA Neurol. 2013, 70, 1520–1530. [Google Scholar] [CrossRef]
- Duyao, M.; Ambrose, C.; Myers, R.; Novelletto, A.; Persichetti, F.; Frontali, M.; Folstein, S.; Ross, C.; Franz, M.; Abbott, M. Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat. Genet. 1993, 4, 387–392. [Google Scholar] [CrossRef] [PubMed]
- McKinstry, S.U.; Karadeniz, Y.B.; Worthington, A.K.; Hayrapetyan, V.Y.; Ozlu, M.I.; Serafin-Molina, K.; Risher, W.C.; Ustunkaya, T.; Dragatsis, I.; Zeitlin, S.; et al. Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. J. Neurosci. 2014, 34, 9455–9472. [Google Scholar] [CrossRef] [PubMed]
- Jimenez-Sanchez, M.; Licitra, F.; Underwood, B.R.; Rubinsztein, D.C. Huntington’s disease: Mechanisms of pathogenesis and therapeutic strategies. Cold Spring Harb. Perspect. Med. 2017, 7, a024240. [Google Scholar] [CrossRef]
- Sun, Y.; Savanenin, A.; Reddy, P.H.; Liu, Y.F. Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-d-aspartate receptors via post-synaptic density 95. J. Biol. Chem. 2001, 276, 24713–24718. [Google Scholar] [CrossRef]
- Young, A.B.; Greenamyre, J.T.; Hollingsworth, Z.; Albin, R.; D’Amato, C.; Shoulson, I.; Penney, J.B. NMDA receptor losses in putamen from patients with Huntington’s disease. Science 1988, 241, 981–983. [Google Scholar] [CrossRef] [PubMed]
- Albin, R.L.; Young, A.B.; Penney, J.B.; Handelin, B.; Balfour, R.; Anderson, K.D.; Markel, D.S.; Tourtellotte, W.W.; Reiner, A. Abnormalities of striatal projection neurons and N-methyl-d-aspartate receptors in presymptomatic Huntington’s disease. N. Engl. J. Med. 1990, 322, 1293–1298. [Google Scholar] [CrossRef]
- Matsushima, A.; Pineda, S.S.; Crittenden, J.R.; Lee, H.; Galani, K.; Mantero, J.; Tombaugh, G.; Kellis, M.; Heiman, M.; Graybiel, A.M. Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease. Nat. Commun. 2023, 14, 282. [Google Scholar] [CrossRef] [PubMed]
- Cepeda, C.; Ariano, M.A.; Calvert, C.R.; Flores-Hernández, J.; Chandler, S.H.; Leavitt, B.R.; Hayden, M.R.; Levine, M.S. NMDA receptor function in mouse models of Huntington disease. J. Neurosci. Res. 2001, 66, 525–539. [Google Scholar] [CrossRef]
- Ali, N.J.; Levine, M.S. Changes in expression of N-methyl-d-aspartate receptor subunits occur early in the R6/2 mouse model of Huntington’s disease. Dev. Neurosci. 2006, 28, 230–238. [Google Scholar] [CrossRef]
- Jarabek, B.R.; Yasuda, R.P.; Wolfe, B.B. Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington’s mouse model. Brain 2004, 127, 505–516. [Google Scholar] [CrossRef]
- Faideau, M.; Kim, J.; Cormier, K.; Gilmore, R.; Welch, M.; Auregan, G.; Dufour, N.; Guillermier, M.; Brouillet, E.; Hantraye, P.; et al. In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: A correlation with Huntington’s disease subjects. Hum. Mol. Genet. 2010, 19, 3053–3067. [Google Scholar] [CrossRef] [PubMed]
- Heng, M.Y.; Detloff, P.J.; Wang, P.L.; Tsien, J.Z.; Albin, R.L. In vivo evidence for NMDA receptor-mediated excitotoxicity in a murine genetic model of Huntington disease. J. Neurosci. 2009, 29, 3200–3205. [Google Scholar] [CrossRef]
- Lujan, B.; Liu, X.; Wan, Q. Differential roles of GluN2A- and GluN2B-containing NMDA receptors in neuronal survival and death. Int. J. Physiol. Pathophysiol. Pharmacol. 2012, 4, 211–218. [Google Scholar]
- Hardingham, G.E.; Fukunaga, Y.; Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 2002, 5, 405–414. [Google Scholar] [CrossRef]
- Hardingham, G.E.; Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: Implications for neurodegenerative disorders. Nat. Rev. Neurosci. 2010, 11, 682–696. [Google Scholar] [CrossRef]
- Jiang, H.; Poirier, M.A.; Liang, Y.; Pei, Z.; Weiskittel, C.E.; Smith, W.W.; DeFranco, D.B.; Ross, C.A. Depletion of CBP is directly linked with cellular toxicity caused by mutant huntingtin. Neurobiol. Dis. 2006, 23, 543–551. [Google Scholar] [CrossRef] [PubMed]
- Saft, C.; Burgunder, J.-M.; Dose, M.; Jung, H.H.; Katzenschlager, R.; Priller, J.; Nguyen, H.P.; Reetz, K.; Reilmann, R.; Seppi, K.; et al. Symptomatic treatment options for Huntington’s disease (guidelines of the German Neurological Society). Neurol. Res. Pract. 2023, 5, 61. [Google Scholar] [CrossRef] [PubMed]
- Dickson, D.W. Neuropathology of Parkinson disease. Park. Relat. Disord. 2018, 46, S30–S33. [Google Scholar] [CrossRef] [PubMed]
- De Pablo-Fernández, E.; Lees, A.J.; Holton, J.L.; Warner, T.T. Prognosis and neuropathologic correlation of clinical subtypes of Parkinson disease. JAMA Neurol. 2019, 76, 470–479. [Google Scholar] [CrossRef] [PubMed]
- Nagatsua, T.; Sawadab, M. L-Dopa therapy for Parkinson’s disease: Past, present, and future. Park. Relat. Disord. 2009, 15, S3–S8. [Google Scholar] [CrossRef] [PubMed]
- Bastide, M.F.; Meissner, W.G.; Picconi, B.; Fasano, S.; Fernagut, P.-O.; Feyder, M.; Francardo, V.; Alcacer, C.; Ding, Y.; Bram-billa, R.; et al. Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson’s disease. Prog. Neurobiol. 2015, 132, 96–168. [Google Scholar] [CrossRef] [PubMed]
- Marti, M.; Paganini, F.; Stocchi, S.; Mela, F.; Beani, L.; Bianchi, C.; Morari, M. Plasticity of glutamatergic control of striatal acetylcholine release in experimental parkinsonism: Opposite changes at group-II metabotropic and NMDA receptors. J. Neurochem. 2003, 84, 792–802. [Google Scholar] [CrossRef] [PubMed]
- Jones, D.C.; Gunasekar, P.G.; Borowitz, J.L.; Isom, G.E. Dopamine-induced apoptosis is mediated by oxidative stress and is enhanced by cyanide in differentiated PC12 cells. J. Neurochem. 2000, 74, 2296–2304. [Google Scholar] [CrossRef] [PubMed]
- Jourdain, V.A.; Morin, N.; Grégoire, L.; Morissette, M.; Di Paolo, T. Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy. J. Neurosurg. 2015, 123, 1383–1393. [Google Scholar] [CrossRef] [PubMed]
- Verhagen Metman, L.; Blanchet, P.J.; van den Munckhof, P.; Del Dotto, P.; Natté, R.; Chase, T.N. A trial of dextromethorphan in parkinsonian patients with motor response complications. Mov. Disord. 1998, 13, 414–417. [Google Scholar] [CrossRef] [PubMed]
- Rascol, O.; Fabbri, M.; Poewe, W. Amantadine in the treatment of Parkinson’s disease and other movement disorders. Lancet Neurol. 2021, 20, 1048–1056. [Google Scholar] [CrossRef] [PubMed]
- Uitti, R.J.; Rajput, A.H.; Ahlskog, J.E.; Offord, K.P.; Schroeder, D.R.; Ho, M.M.; Prasad, M.; Rajput, A.; Basran, P. Amantadine treatment is an independent predictor of improved survival in Parkinson’s disease. Neurology 1996, 46, 1551–1556. [Google Scholar] [CrossRef] [PubMed]
- Merello, M.; Nouzeilles, M.I.; Cammarota, A.; Leiguarda, R. Effect of memantine (NMDA antagonist) on Parkinson’s disease: A double-blind crossover randomized study. Clin. Neuropharmacol. 1999, 22, 273–276. [Google Scholar] [PubMed]
- Dembitsky, V.M.; Gloriozova, T.A.; Poroikov, V.V. Pharmacological profile of natural and synthetic compounds with rigid adamantane-based scaffolds as potential agents for the treatment of neurodegenerative diseases. Biochem. Biophys. Res. Commun. 2020, 529, 1225–1241. [Google Scholar] [CrossRef]
- Samnick, S.; Ametamey, S.; Leenders, K.L.; Vontobel, P.; Quack, G.; Parsons, C.G.; Neu, H.; Schubiger, P.A. Electrophysiolog-ical study, biodistribution in mice, and preliminary PET evaluation in a rhesus monkey of 1-amino-3-[18F]fluoromethyl-5-methyl-adamantane (18F-MEM): A potential radioligand for mapping the NMDA-receptor complex. Nucl. Med. Biol. 1998, 25, 323–330. [Google Scholar] [CrossRef] [PubMed]
- Ametamey, S.M.; Samnick, S.; Leenders, K.L.; Vontobel, P.; Quack, G.; Parsons, C.G.; Schubiger, P.A. Fluorine-18 radiolabel-ling, biodistribution studies and preliminary PET evaluation of a new memantine derivative for imaging the NMDA receptor. J. Recept. Signal Transduct. Res. 1999, 19, 129–141. [Google Scholar] [CrossRef] [PubMed]
- Ametamey, S.M.; Bruehlmeier, M.; Kneifel, S.; Kokic, M.; Honer, M.; Arigoni, M.; Buck, A.; Burger, C.; Samnick, S.; Quack, G.; et al. PET studies of 18F-memantine in healthy volunteers. Nucl. Med. Biol. 2002, 29, 227–231. [Google Scholar] [CrossRef]
- Weissman, A.D.; Casanova, M.F.; Kleinman, J.E.; De Souza, E.B. PCP and sigma receptors in brain are not altered after repeated exposure to PCP in humans. Neuropsychopharmacology 1991, 4, 95–102. [Google Scholar] [PubMed]
- Salabert, A.-S.; Fonta, C.; Fontan, C.; Adel, D.; Alonso, M.; Pestourie, C.; Belhadj-Tahar, H.; Tafani, M.; Payoux, P. Radio-labeling of [18F]-fluoroethylnormemantine and initial in vivo evaluation of this innovative PET tracer for imaging the PCP sites of NMDA receptors. Nucl. Med. Biol. 2015, 42, 643–653. [Google Scholar] [CrossRef] [PubMed]
- Salabert, A.-S.; Mora-Ramirez, E.; Beaurain, M.; Alonso, M.; Fontan, C.; Tahar, H.B.; Boizeau, M.L.; Tafani, M.; Bardiès, M.; Payoux, P. Evaluation of [18F]FNM biodistribution and dosimetry based on whole-body PET imaging of rats. Nucl. Med. Biol. 2018, 59, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Beaurain, M.; Talmont, F.; Pierre, D.; Péran, P.; Boucher, S.; Hitzel, A.; Rols, M.-P.; Cuvillier, O.; Payoux, P.; Salabert, A.-S. Pharmacological characterization of [18F]-FNM and evaluation of NMDA receptors activation in a rat brain injury model. Mol. Imaging Biol. 2023, 25, 692–703. [Google Scholar] [CrossRef] [PubMed]
- Zarate, C.A.; Singh, J.B.; Carlson, P.J.; Brutsche, N.E.; Ameli, R.; Luckenbaugh, D.A.; Charney, D.S.; Manji, H.K. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 2006, 63, 856–864. [Google Scholar] [CrossRef] [PubMed]
- aan het Rot, M.; Collins, K.A.; Murrough, J.W.; Perez, A.M.; Reich, D.L.; Charney, D.S.; Mathew, S.J. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol. Psychiatry 2010, 67, 139–145. [Google Scholar] [CrossRef] [PubMed]
- Amat, J.; Dolzani, S.D.; Tilden, S.; Christianson, J.P.; Kubala, K.H.; Bartholomay, K.; Sperr, K.; Ciancio, N.; Watkins, L.R.; Maier, S.F. Previous ketamine produces an enduring blockade of neurochemical and behavioral effects of uncontrollable stress. J. Neurosci. 2016, 36, 153–161. [Google Scholar] [CrossRef]
- Brachman, R.A.; McGowan, J.C.; Perusini, J.N.; Lim, S.C.; Pham, T.H.; Faye, C.; Gardier, A.M.; Mendez-David, I.; David, D.J.; Hen, R.; et al. Ketamine as a prophylactic against stress-induced depressive-like behavior. Biol. Psychiatr. 2016, 79, 776–786. [Google Scholar] [CrossRef] [PubMed]
- McGowan, J.C.; LaGamma, C.T.; Lim, S.C.; Tsitsiklis, M.; Neria, Y.; Brachman, R.A.; Denny, C.A. Prophylactic ketamine attenuates learned fear. Neuropsychopharmacology 2017, 42, 1577–1589. [Google Scholar] [CrossRef]
- Chen, B.K.; Le Pen, G.; Eckmier, A.; Rubinstenn, G.; Jay, T.M.; Denny, C.A. Fluoroethylnormemantine, a novel derivative of memantine, facilitates extinction learning without sensorimotor deficits. Int. J. Neuropychopharmacol. 2021, 24, 519–531. [Google Scholar] [CrossRef] [PubMed]
- Chen, B.K.; Luna, V.M.; Shannon, M.E.; Hunsberger, H.C.; Mastrodonato, A.; Stackmann, M.; McGowan, J.C.; Rubinstenn, G.; Denny, C.A. Fluoroethylnormemantine, a novel NMDA receptor antagonist, for the prevention and treatment of stress-induced maladaptive behavior. Biol. Psychiatr. 2021, 90, 458–472. [Google Scholar] [CrossRef]
- Maurice, T.; Phan, V.-L.; Privat, A. The anti-amnesic effects of sigma1 (σ1) receptor agonists confirmed by in vivo antisense strategy in the mouse. Brain Res. 2001, 898, 113–121. [Google Scholar] [CrossRef] [PubMed]
- Couly, S.; Denus, M.; Bouchet, M.; Rubinstenn, G.; Maurice, T. Anti-amnesic and neuroprotective effects of fluoroethyl-normemantine in a pharmacological mouse model of Alzheimer’s disease. Int. J. Neuropsychopharmacol. 2020, 24, 142–157. [Google Scholar] [CrossRef] [PubMed]
- Jankowsky, J.L.; Slunt, H.H.; Ratovitski, T.; Jenkins, N.A.; Copeland, N.G.; Borchelt, D.R. Co-expression of multiple transgenes in mouse CNS: A comparison of strategies. Biomol. Eng. 2001, 17, 157–165. [Google Scholar] [CrossRef] [PubMed]
- Carles, A.; Freyssin, A.; Guehairia, S.; Reguero, T.; Rubinstenn, G.; Maurice, T. Neuroprotective effects of Fluoroethylnormemantine (FENM) after chronic infusion by Alzet pumps in the Aß25-35 mouse model of Alzheimer’s disease. Neuroscience Meeting Planner; Society for Neuroscience: San Diego, CA, USA, 2022; Program No. 197.20. Online. [Google Scholar]
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Carles, A.; Freyssin, A.; Perin-Dureau, F.; Rubinstenn, G.; Maurice, T. Targeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases. Int. J. Mol. Sci. 2024, 25, 3733. https://doi.org/10.3390/ijms25073733
Carles A, Freyssin A, Perin-Dureau F, Rubinstenn G, Maurice T. Targeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases. International Journal of Molecular Sciences. 2024; 25(7):3733. https://doi.org/10.3390/ijms25073733
Chicago/Turabian StyleCarles, Allison, Aline Freyssin, Florent Perin-Dureau, Gilles Rubinstenn, and Tangui Maurice. 2024. "Targeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases" International Journal of Molecular Sciences 25, no. 7: 3733. https://doi.org/10.3390/ijms25073733
APA StyleCarles, A., Freyssin, A., Perin-Dureau, F., Rubinstenn, G., & Maurice, T. (2024). Targeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases. International Journal of Molecular Sciences, 25(7), 3733. https://doi.org/10.3390/ijms25073733