1932

Abstract

Excitatory/inhibitory (E/I) balance, defined as the balance between excitation and inhibition of synaptic activity in a neuronal network, accounts in part for the normal functioning of the brain, controlling, for example, normal spike rate. In many pathological conditions, this fine balance is perturbed, leading to excessive or diminished excitation relative to inhibition, termed E/I imbalance, reflected in network dysfunction. E/I imbalance has emerged as a contributor to neurological disorders that occur particularly at the extremes of life, including autism spectrum disorder and Alzheimer's disease, pointing to the vulnerability of neuronal networks at these critical life stages. Hence, it is important to develop approaches to rebalance neural networks. In this review, we describe emerging therapies that can normalize the E/I ratio or the underlying abnormality that contributes to the imbalance in electrical activity, thus improving neurological function in these maladies.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-032320-015420
2021-01-06
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/61/1/annurev-pharmtox-032320-015420.html?itemId=/content/journals/10.1146/annurev-pharmtox-032320-015420&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Shewcraft RA, Dean HL, Fabiszak MM, Hagan MA, Wong YT, Pesaran B 2020. Excitatory/inhibitory responses shape coherent neuronal dynamics driven by optogenetic stimulation in the primate brain. J. Neurosci. 40:2056–68
    [Google Scholar]
  2. 2. 
    Lee E, Lee J, Kim E 2017. Excitation/inhibition imbalance in animal models of autism spectrum disorders. Biol. Psychiatry 81:838–47
    [Google Scholar]
  3. 3. 
    Rubenstein JL, Merzenich MM. 2003. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2:255–67
    [Google Scholar]
  4. 4. 
    Styr B, Slutsky I. 2018. Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer's disease. Nat. Neurosci. 21:463–73
    [Google Scholar]
  5. 5. 
    O'Donnell C, Gonçalves JT, Portera-Cailliau C, Sejnowski TJ 2017. Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders. eLife 6:e26724
    [Google Scholar]
  6. 6. 
    Alcami P, Pereda AE. 2019. Beyond plasticity: the dynamic impact of electrical synapses on neural circuits. Nat. Rev. Neurosci. 20:253–71
    [Google Scholar]
  7. 7. 
    Südhof TC. 2018. Towards an understanding of synapse formation. Neuron 100:276–93
    [Google Scholar]
  8. 8. 
    Curtis DR, Watkins JC. 1960. The excitation and depression of spinal neurones by structurally related amino acids. J. Neurochem. 6:117–41
    [Google Scholar]
  9. 9. 
    Szczurowska E, Mareš P. 2013. NMDA and AMPA receptors: development and status epilepticus. Physiol. Res. 62:Suppl. 1S21–38
    [Google Scholar]
  10. 10. 
    Guerriero RM, Giza CC, Rotenberg A 2015. Glutamate and GABA imbalance following traumatic brain injury. Curr. Neurol. Neurosci. Rep. 15:27
    [Google Scholar]
  11. 11. 
    Boivin JR, Nedivi E. 2018. Functional implications of inhibitory synapse placement on signal processing in pyramidal neuron dendrites. Curr. Opin. Neurobiol. 51:16–22
    [Google Scholar]
  12. 12. 
    Kubota Y. 2014. Untangling GABAergic wiring in the cortical microcircuit. Curr. Opin. Neurobiol. 26:7–14
    [Google Scholar]
  13. 13. 
    DeFelipe J, Farinas I. 1992. The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs. Prog. Neurobiol. 39:563–607
    [Google Scholar]
  14. 14. 
    Takamori S, Rhee JS, Rosenmund C, Jahn R 2000. Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons. Nature 407:189–94
    [Google Scholar]
  15. 15. 
    Coley AA, Gao WJ. 2018. PSD95: a synaptic protein implicated in schizophrenia or autism. ? Prog. Neuropsychopharmacol. Biol. Psychiatry 82:187–94
    [Google Scholar]
  16. 16. 
    Chua JJ, Kindler S, Boyken J, Jahn R 2010. The architecture of an excitatory synapse. J. Cell Sci. 123:819–23
    [Google Scholar]
  17. 17. 
    Chaudhry FA, Reimer RJ, Bellocchio EE, Danbolt NC, Osen KK et al. 1998. The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J. Neurosci. 18:9733–50
    [Google Scholar]
  18. 18. 
    Collingridge GL, Isaac JT, Wang YT 2004. Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5:952–62
    [Google Scholar]
  19. 19. 
    Essrich C, Lorez M, Benson JA, Fritschy JM, Lüscher B 1998. Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin. Nat. Neurosci. 1:563–71
    [Google Scholar]
  20. 20. 
    Kneussel M, Betz H. 2000. Receptors, gephyrin and gephyrin-associated proteins: novel insights into the assembly of inhibitory postsynaptic membrane specializations. J. Physiol. 525:Part 11–9
    [Google Scholar]
  21. 21. 
    Gorlewicz A, Kaczmarek L. 2018. Pathophysiology of trans-synaptic adhesion molecules: implications for epilepsy. Front. Cell Dev. Biol. 6:119
    [Google Scholar]
  22. 22. 
    Reiner A, Levitz J. 2018. Glutamatergic signaling in the central nervous system: ionotropic and metabotropic receptors in concert. Neuron 98:1080–98
    [Google Scholar]
  23. 23. 
    Yuste R. 2011. Dendritic spines and distributed circuits. Neuron 71:772–81
    [Google Scholar]
  24. 24. 
    Tonnesen J, Nagerl UV. 2016. Dendritic spines as tunable regulators of synaptic signals. Front. Psychiatry 7:101
    [Google Scholar]
  25. 25. 
    Spruston N. 2008. Pyramidal neurons: dendritic structure and synaptic integration. Nat. Rev. Neurosci. 9:206–21
    [Google Scholar]
  26. 26. 
    Weber JP, Andrásfalvy BK, Polito M, Magó A, Ujfalussy BB, Makara JK 2016. Location-dependent synaptic plasticity rules by dendritic spine cooperativity. Nat. Commun. 7:11380
    [Google Scholar]
  27. 27. 
    Chklovskii DB, Mel BW, Svoboda K 2004. Cortical rewiring and information storage. Nature 431:782–88
    [Google Scholar]
  28. 28. 
    Hamilton AM, Oh WC, Vega-Ramirez H, Stein IS, Hell JW et al. 2012. Activity-dependent growth of new dendritic spines is regulated by the proteasome. Neuron 74:1023–30
    [Google Scholar]
  29. 29. 
    Ruthazer ES. 2005. You're perfect, now change—redefining the role of developmental plasticity. Neuron 45:825–28
    [Google Scholar]
  30. 30. 
    Navlakha S, Barth AL, Bar-Joseph Z 2015. Decreasing-rate pruning optimizes the construction of efficient and robust distributed networks. PLOS Comput. Biol. 11:e1004347
    [Google Scholar]
  31. 31. 
    Holtmaat A, Svoboda K. 2009. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat. Rev. Neurosci 10:647–58 Erratum. Nat. Rev. Neurosci. 2009 10:10759
    [Google Scholar]
  32. 32. 
    Tremblay R, Lee S, Rudy B 2016. GABAergic interneurons in the neocortex: from cellular properties to circuits. Neuron 91:260–92
    [Google Scholar]
  33. 33. 
    Pelkey KA, Chittajallu R, Craig MT, Tricoire L, Wester JC, McBain CJ 2017. Hippocampal GABAergic inhibitory interneurons. Physiol. Rev. 97:1619–747
    [Google Scholar]
  34. 34. 
    Rudy B, Fishell G, Lee S, Hjerling-Leffler J 2011. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev. Neurobiol. 71:45–61
    [Google Scholar]
  35. 35. 
    Petilla Interneuron Nomenclature Group, Ascoli GA, Alonso-Nanclares L, Anderson SA, Barrionuevo G et al. 2008. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9:557–68
    [Google Scholar]
  36. 36. 
    Kawaguchi Y, Kubota Y. 1997. GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb. Cortex 7:476–86
    [Google Scholar]
  37. 37. 
    Buzsáki G, Wang X-J. 2012. Mechanisms of gamma oscillations. Annu. Rev. Neurosci. 35:203–25
    [Google Scholar]
  38. 38. 
    Klausberger T, Somogyi P. 2008. Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 321:53–57
    [Google Scholar]
  39. 39. 
    Nelson SB, Valakh V. 2015. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 87:684–98
    [Google Scholar]
  40. 40. 
    Vogels TP, Sprekeler H, Zenke F, Clopath C, Gerstner W 2011. Inhibitory plasticity balances excitation and inhibition in sensory pathways and memory networks. Science 334:1569–73
    [Google Scholar]
  41. 41. 
    He H-y, Cline HT 2019. What is excitation/inhibition and how is it regulated? A case of the elephant and the wisemen. J. Exp. Neurosci. 13: https://doi.org/10.1177/1179069519859371
    [Crossref] [Google Scholar]
  42. 42. 
    Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB 1998. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391:892–96
    [Google Scholar]
  43. 43. 
    Opris I, Casanova MF. 2014. Prefrontal cortical minicolumn: from executive control to disrupted cognitive processing. Brain 137:1863–75
    [Google Scholar]
  44. 44. 
    Raghanti MA, Spocter MA, Butti C, Hof PR, Sherwood CC 2010. A comparative perspective on minicolumns and inhibitory GABAergic interneurons in the neocortex. Front. Neuroanat. 4:3
    [Google Scholar]
  45. 45. 
    Tatti R, Haley MS, Swanson OK, Tselha T, Maffei A 2017. Neurophysiology and regulation of the balance between excitation and inhibition in neocortical circuits. Biol. Psychiatry 81:821–31
    [Google Scholar]
  46. 46. 
    Beierlein M, Gibson JR, Connors BW 2000. A network of electrically coupled interneurons drives synchronized inhibition in neocortex. Nat. Neurosci. 3:904–10
    [Google Scholar]
  47. 47. 
    Gao R, Penzes P. 2015. Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. Curr. Mol. Med. 15:146–67
    [Google Scholar]
  48. 48. 
    Foss-Feig JH, Adkinson BD, Ji JL, Yang G, Srihari VH et al. 2017. Searching for cross-diagnostic convergence: neural mechanisms governing excitation and inhibition balance in schizophrenia and autism spectrum disorders. Biol. Psychiatry 81:848–61
    [Google Scholar]
  49. 49. 
    Antoine MW, Langberg T, Schnepel P, Feldman DE 2019. Increased excitation-inhibition ratio stabilizes synapse and circuit excitability in four autism mouse models. Neuron 101:648–61.e4
    [Google Scholar]
  50. 50. 
    Park HR, Lee JM, Moon HE, Lee DS, Kim B-N et al. 2016. A short review on the current understanding of autism spectrum disorders. Exp. Neurobiol. 25:1–13
    [Google Scholar]
  51. 51. 
    Bateup HS, Takasaki KT, Saulnier JL, Denefrio CL, Sabatini BL 2011. Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J. Neurosci. 31:8862–69
    [Google Scholar]
  52. 52. 
    Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL 2013. Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron 78:510–22
    [Google Scholar]
  53. 53. 
    Wong M, Ess KC, Uhlmann EJ, Jansen LA, Li W et al. 2003. Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Ann. Neurol. 54:251–56
    [Google Scholar]
  54. 54. 
    Lozovaya N, Gataullina S, Tsintsadze T, Tsintsadze V, Pallesi-Pocachard E et al. 2014. Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model. Nat. Commun. 5:4563
    [Google Scholar]
  55. 55. 
    Okamoto S-i, Prikhodko O, Pina-Crespo J, Adame A, McKercher SR et al. 2019. NitroSynapsin for the treatment of neurological manifestations of tuberous sclerosis complex in a rodent model. Neurobiol. Dis. 127:390–97
    [Google Scholar]
  56. 56. 
    Lozovaya N, Nardou R, Tyzio R, Chiesa M, Pons-Bennaceur A et al. 2019. Early alterations in a mouse model of Rett syndrome: The GABA developmental shift is abolished at birth. Sci. Rep. 9:9276
    [Google Scholar]
  57. 57. 
    Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW et al. 2010. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143:527–39
    [Google Scholar]
  58. 58. 
    Katz DM, Berger-Sweeney JE, Eubanks JH, Justice MJ, Neul JL et al. 2012. Preclinical research in Rett syndrome: setting the foundation for translational success. Dis. Model. Mech. 5:733–45
    [Google Scholar]
  59. 59. 
    Banerjee A, Rikhye RV, Breton-Provencher V, Tang X, Li C et al. 2016. Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome. PNAS 113:E7287–96
    [Google Scholar]
  60. 60. 
    Nageshappa S, Carromeu C, Trujillo CA, Mesci P, Espuny-Camacho I et al. 2016. Altered neuronal network and rescue in a human MECP2 duplication model. Mol. Psychiatry 21:178–88
    [Google Scholar]
  61. 61. 
    Ebert DH, Greenberg ME. 2013. Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493:327–37
    [Google Scholar]
  62. 62. 
    Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A et al. 2011. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat. Med. 17:1657–62
    [Google Scholar]
  63. 63. 
    Mabb AM, Judson MC, Zylka MJ, Philpot BD 2011. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci 34:293–303
    [Google Scholar]
  64. 64. 
    Zoghbi HY, Bear MF. 2012. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 4:a009886
    [Google Scholar]
  65. 65. 
    Sato M, Stryker MP. 2010. Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a. . PNAS 107:5611–16
    [Google Scholar]
  66. 66. 
    Yashiro K, Riday TT, Condon KH, Roberts AC, Bernardo DR et al. 2009. Ube3a is required for experience-dependent maturation of the neocortex. Nat. Neurosci. 12:777–83
    [Google Scholar]
  67. 67. 
    Pilpel Y, Kolleker A, Berberich S, Ginger M, Frick A et al. 2009. Synaptic ionotropic glutamate receptors and plasticity are developmentally altered in the CA1 field of Fmr1 knockout mice. J. Physiol. 587:787–804
    [Google Scholar]
  68. 68. 
    Bear MF, Huber KM, Warren ST 2004. The mGluR theory of fragile X mental retardation. Trends Neurosci 27:370–77
    [Google Scholar]
  69. 69. 
    Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P et al. 2016. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci. Transl. Med. 8:321ra5
    [Google Scholar]
  70. 70. 
    Jacquemont S, Curie A, des Portes V, Torrioli MG, Berry-Kravis E et al. 2011. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci. Transl. Med. 3:64ra1
    [Google Scholar]
  71. 71. 
    Erickson CA, Davenport MH, Schaefer TL, Wink LK, Pedapati EV et al. 2017. Fragile X targeted pharmacotherapy: lessons learned and future directions. J. Neurodev. Disord. 9:7
    [Google Scholar]
  72. 72. 
    Varoqueaux F, Aramuni G, Rawson RL, Mohrmann R, Missler M et al. 2006. Neuroligins determine synapse maturation and function. Neuron 51:741–54
    [Google Scholar]
  73. 73. 
    Schmeisser MJ, Ey E, Wegener S, Bockmann J, Stempel AV et al. 2012. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486:256–60
    [Google Scholar]
  74. 74. 
    Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS et al. 2011. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3.Hum. Mol. . Genet 20:3093–108
    [Google Scholar]
  75. 75. 
    Jang S, Lee H, Kim E 2017. Synaptic adhesion molecules and excitatory synaptic transmission. Curr. Opin. Neurobiol. 45:45–50
    [Google Scholar]
  76. 76. 
    Rinaldi T, Kulangara K, Antoniello K, Markram H 2007. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. PNAS 104:13501–6
    [Google Scholar]
  77. 77. 
    Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E et al. 2007. NaV1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J. Neurosci. 27:5903–14
    [Google Scholar]
  78. 78. 
    Ouss L, Leunen D, Laschet J, Chemaly N, Barcia G et al. 2019. Autism spectrum disorder and cognitive profile in children with Dravet syndrome: delineation of a specific phenotype. Epilepsia Open 4:40–53
    [Google Scholar]
  79. 79. 
    Catterall WA. 2018. Dravet syndrome: a sodium channel interneuronopathy. Curr. Opin. Physiol. 2:42–50
    [Google Scholar]
  80. 80. 
    Moore CM, Biederman J, Wozniak J, Mick E, Aleardi M et al. 2006. Differences in brain chemistry in children and adolescents with attention deficit hyperactivity disorder with and without comorbid bipolar disorder: a proton magnetic resonance spectroscopy study. Am. J. Psychiatry 163:316–18
    [Google Scholar]
  81. 81. 
    Won H, Mah W, Kim E, Kim JW, Hahm EK et al. 2011. GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice. Nat. Med. 17:566–72
    [Google Scholar]
  82. 82. 
    Tu S, Akhtar MW, Escorihuela RM, Amador-Arjona A, Swarup V et al. 2017. NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism. Nat. Commun. 8:1488
    [Google Scholar]
  83. 83. 
    Harrington AJ, Raissi A, Rajkovich K, Berto S, Kumar J et al. 2016. MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. eLife 5:e20059
    [Google Scholar]
  84. 84. 
    Cardoso C, Boys A, Parrini E, Mignon-Ravix C, McMahon JM et al. 2009. Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion. Neurology 72:784–92
    [Google Scholar]
  85. 85. 
    Bienvenu T, Diebold B, Chelly J, Isidor B 2013. Refining the phenotype associated with MEF2C point mutations. Neurogenetics 14:71–75
    [Google Scholar]
  86. 86. 
    Mayer C, Hafemeister C, Bandler RC, Machold R, Batista Brito R et al. 2018. Developmental diversification of cortical inhibitory interneurons. Nature 555:457–62
    [Google Scholar]
  87. 87. 
    Yang CR, Seamans JK, Gorelova N 1999. Developing a neuronal model for the pathophysiology of schizophrenia based on the nature of electrophysiological actions of dopamine in the prefrontal cortex. Neuropsychopharmacology 21:161–94
    [Google Scholar]
  88. 88. 
    Coyle JT. 2012. NMDA receptor and schizophrenia: a brief history. Schizophr. Bull. 38:920–26
    [Google Scholar]
  89. 89. 
    Goff DC, Coyle JT. 2001. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am. J. Psychiatry 158:1367–77
    [Google Scholar]
  90. 90. 
    de Jonge JC, Vinkers CH, Hulshoff Pol HE, Marsman A 2017. GABAergic mechanisms in schizophrenia: linking postmortem and in vivo studies. Front. Psychiatry 8:118
    [Google Scholar]
  91. 91. 
    Fatemi SH, Folsom TD, Thuras PD 2017. GABAA and GABAB receptor dysregulation in superior frontal cortex of subjects with schizophrenia and bipolar disorder. Synapse 71: https://doi.org/10.1002/syn.21973
    [Crossref] [Google Scholar]
  92. 92. 
    Uhlhaas PJ, Singer W. 2013. High-frequency oscillations and the neurobiology of schizophrenia. Dialogues Clin. Neurosci. 15:301–13
    [Google Scholar]
  93. 93. 
    Grent-’t-Jong T, Gross J, Goense J, Wibral M, Gajwani R et al. 2018. Resting-state gamma-band power alterations in schizophrenia reveal E/I-balance abnormalities across illness-stages. eLife 7:e37799
    [Google Scholar]
  94. 94. 
    Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR et al. 2012. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 74:467–74
    [Google Scholar]
  95. 95. 
    Dickerson BC, Salat DH, Greve DN, Chua EF, Rand-Giovannetti E et al. 2005. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology 65:404–11
    [Google Scholar]
  96. 96. 
    Oran Y, Bar-Gad I. 2018. Loss of balance between striatal feedforward inhibition and corticostriatal excitation leads to tremor. J. Neurosci. 38:1699–710
    [Google Scholar]
  97. 97. 
    McGregor MM, Nelson AB. 2019. Circuit mechanisms of Parkinson's disease. Neuron 101:1042–56
    [Google Scholar]
  98. 98. 
    Diógenes MJ, Dias RB, Rombo DM, Vicente Miranda H, Maiolino F et al. 2012. Extracellular α-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J. Neurosci. 32:11750–62
    [Google Scholar]
  99. 99. 
    Ferreira DG, Temido-Ferreira M, Vicente Miranda H, Batalha VL, Coelho JE et al. 2017. α-Synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B. Nat. Neurosci. 20:1569–79
    [Google Scholar]
  100. 100. 
    Kiernan MC, Ziemann U, Eisen A 2019. Amyotrophic lateral sclerosis: origins traced to impaired balance between neural excitation and inhibition in the neonatal period. Muscle Nerve 60:232–35
    [Google Scholar]
  101. 101. 
    Foerster BR, Pomper MG, Callaghan BC, Petrou M, Edden RA et al. 2013. An imbalance between excitatory and inhibitory neurotransmitters in amyotrophic lateral sclerosis revealed by use of 3-T proton magnetic resonance spectroscopy. JAMA Neurol 70:1009–16
    [Google Scholar]
  102. 102. 
    Lipton SA, Sucher NJ, Kaiser PK, Dreyer EB 1991. Synergistic effects of HIV coat protein and NMDA receptor-mediated neurotoxicity. Neuron 7:111–18
    [Google Scholar]
  103. 103. 
    Green MV, Raybuck JD, Zhang X, Wu MM, Thayer SA 2019. Scaling synapses in the presence of HIV. Neurochem. Res. 44:234–46
    [Google Scholar]
  104. 104. 
    Dreyer EB, Kaiser PK, Offermann JT, Lipton SA 1990. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science 248:364–67
    [Google Scholar]
  105. 105. 
    Dreyer EB, Lipton SA. 1995. The coat protein gp120 of HIV-1 inhibits astrocyte uptake of excitatory amino acids via macrophage arachidonic acid. Eur. J. Neurosci. 7:2502–7
    [Google Scholar]
  106. 106. 
    Choi DW. 1992. Excitotoxic cell death. J. Neurobiol. 23:1261–76
    [Google Scholar]
  107. 107. 
    Xu H, Bae M, Tovar-y-Romo LB, Patel N, Bandaru VV et al. 2011. The human immunodeficiency virus coat protein gp120 promotes forward trafficking and surface clustering of NMDA receptors in membrane microdomains. J. Neurosci. 31:17074–90
    [Google Scholar]
  108. 108. 
    Melendez RI, Roman C, Capo-Velez CM, Lasalde-Dominicci JA 2016. Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice. J. Neurovirol. 22:358–65
    [Google Scholar]
  109. 109. 
    Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM et al. 2016. Incidence and impact of subclinical epileptiform activity in Alzheimer's disease. Ann. Neurol. 80:858–70
    [Google Scholar]
  110. 110. 
    Vossel KA, Beagle AJ, Rabinovici GD, Shu H, Lee SE et al. 2013. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol 70:1158–66
    [Google Scholar]
  111. 111. 
    Moehlmann T, Winkler E, Xia X, Edbauer D, Murrell J et al. 2002. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ42 production. PNAS 99:8025–30
    [Google Scholar]
  112. 112. 
    Lam AD, Deck G, Goldman A, Eskandar EN, Noebels J, Cole AJ 2017. Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease. Nat. Med. 23:678–80
    [Google Scholar]
  113. 113. 
    Mondadori CRA, Buchmann A, Mustovic H, Schmidt CF, Boesiger P et al. 2006. Enhanced brain activity may precede the diagnosis of Alzheimer's disease by 30 years. Brain 129:Part 112908–22
    [Google Scholar]
  114. 114. 
    Ghatak S, Dolatabadi N, Trudler D, Zhang X, Wu Y et al. 2019. Mechanisms of hyperexcitability in Alzheimer's disease hiPSC-derived neurons and cerebral organoids versus isogenic control. eLife 8:e50333
    [Google Scholar]
  115. 115. 
    Park J, Wetzel I, Marriott I, Dreau D, D'Avanzo C et al. 2018. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer's disease. Nat. Neurosci. 21:941–51
    [Google Scholar]
  116. 116. 
    Palop JJ, Mucke L. 2016. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 17:777–92
    [Google Scholar]
  117. 117. 
    Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW et al. 2013. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. PNAS 110:E2518–27
    [Google Scholar]
  118. 118. 
    Angulo MC, Kozlov AS, Charpak S, Audinat E 2004. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J. Neurosci. 24:6920–27
    [Google Scholar]
  119. 119. 
    Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G 2004. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43:729–43
    [Google Scholar]
  120. 120. 
    Hamilton NB, Attwell D. 2010. Do astrocytes really exocytose neurotransmitters. ? Nat. Rev. Neurosci. 11:227–38
    [Google Scholar]
  121. 121. 
    Araque A, Sanzgiri RP, Parpura V, Haydon PG 1998. Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J. Neurosci. 18:6822–29
    [Google Scholar]
  122. 122. 
    Hardingham GE, Bading H. 2010. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11:682–96
    [Google Scholar]
  123. 123. 
    Palop JJ, Mucke L. 2010. Amyloid-β-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat. Neurosci. 13:812–18
    [Google Scholar]
  124. 124. 
    Pennisi G, Ferri R, Cantone M, Lanza G, Pennisi M et al. 2011. A review of transcranial magnetic stimulation in vascular dementia. Dement. Geriatr. Cogn. Disord. 31:71–80
    [Google Scholar]
  125. 125. 
    Won SJ, Kim DY, Gwag BJ 2002. Cellular and molecular pathways of ischemic neuronal death. J. Biochem. Mol. Biol. 35:67–86
    [Google Scholar]
  126. 126. 
    Chen H-SV, Lipton SA. 2006. The chemical biology of clinically tolerated NMDA receptor antagonists. J. Neurochem. 97:1611–26
    [Google Scholar]
  127. 127. 
    Lipton SA. 2004. Concepts: turning down but not off. Nature 428:473
    [Google Scholar]
  128. 128. 
    Zukin RS, Bennett MV. 1995. Alternatively spliced isoforms of the NMDARI receptor subunit. Trends Neurosci 18:306–13
    [Google Scholar]
  129. 129. 
    Lipton SA. 2006. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat. Rev. Drug Discov. 5:160–70
    [Google Scholar]
  130. 130. 
    Johnson JW, Ascher P. 1987. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–31
    [Google Scholar]
  131. 131. 
    Mayer ML, Westbrook GL, Guthrie PB 1984. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309:261–63
    [Google Scholar]
  132. 132. 
    Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM et al. 2010. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62:405–96
    [Google Scholar]
  133. 133. 
    Choi Y-B, Tenneti L, Le DA, Ortiz J, Bai G, Chen H-SV, Lipton SA 2000. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nat. Neurosci. 3:15–21
    [Google Scholar]
  134. 134. 
    Chen H-SV, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S et al. 1992. Open-channel block of N-methyl-d-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J. Neurosci. 12:4427–36
    [Google Scholar]
  135. 135. 
    Chen H-SV, Lipton SA. 1997. Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism. J. Physiol. 499:Part 127–46
    [Google Scholar]
  136. 136. 
    Parsons CG, Danysz W, Quack G 1999. Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 38:735–67
    [Google Scholar]
  137. 137. 
    Rammes G, Rupprecht R, Ferrari U, Zieglgänsberger W, Parsons CG 2001. The N-methyl-d-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT3 receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci. Lett. 306:81–84
    [Google Scholar]
  138. 138. 
    Rogawski MA, Wenk GL. 2003. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease. CNS Drug Rev 9:275–308
    [Google Scholar]
  139. 139. 
    Aracava Y, Pereira EF, Maelicke A, Albuquerque EX 2005. Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than N-methyl-d-aspartate receptors in rat hippocampal neurons. J. Pharmacol. Exp. Ther. 312:31195–205
    [Google Scholar]
  140. 140. 
    Yakel JL, Shao XM, Jackson MB 1991. Activation and desensitization of the 5-HT3 receptor in a rat glioma x mouse neuroblastoma hybrid cell. J. Physiol. 436:293–308
    [Google Scholar]
  141. 141. 
    Banerjee P, Samoriski G, Gupta S 2005. Comments on “Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than N-methyl-d-aspartate receptors in rat hippocampal neurons”. J. Pharmacol. Exp. Ther. 313:2928–33
    [Google Scholar]
  142. 142. 
    Xia P, Chen H-SV, Zhang D, Lipton SA 2010. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J. Neurosci. 30:11246–50
    [Google Scholar]
  143. 143. 
    Martina M, Comas T, Mealing GA 2013. Selective pharmacological modulation of pyramidal neurons and interneurons in the CA1 region of the rat hippocampus. Front. Pharmacol. 4:24
    [Google Scholar]
  144. 144. 
    Lipton SA. 2007. Pathologically activated therapeutics for neuroprotection. Nat. Rev. Neurosci. 8:803–8
    [Google Scholar]
  145. 145. 
    Song X, Jensen MO, Jogini V, Stein RA, Lee CH et al. 2018. Mechanism of NMDA receptor channel block by MK-801 and memantine. Nature 556:515–19
    [Google Scholar]
  146. 146. 
    Widman AJ, McMahon LL. 2018. Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. PNAS 115:E3007–16
    [Google Scholar]
  147. 147. 
    Autry AE, Adachi M, Nosyreva E, Na ES, Los MF et al. 2011. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475:91–95
    [Google Scholar]
  148. 148. 
    Emnett CM, Eisenman LN, Taylor AM, Izumi Y, Zorumski CF, Mennerick S 2013. Indistinguishable synaptic pharmacodynamics of the N-methyl-d-aspartate receptor channel blockers memantine and ketamine. Mol. Pharmacol. 84:935–47
    [Google Scholar]
  149. 149. 
    Glasgow NG, Povysheva NV, Azofeifa AM, Johnson JW 2017. Memantine and ketamine differentially alter NMDA receptor desensitization. J. Neurosci. 37:9686–704
    [Google Scholar]
  150. 150. 
    Takahashi H, Xia P, Cui J, Talantova M, Bodhinathan K et al. 2015. Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease. Sci. Rep. 5:14781
    [Google Scholar]
  151. 151. 
    Takahashi H, Shin Y, Cho SJ, Zago WM, Nakamura T et al. 2007. Hypoxia enhances S-nitrosylation-mediated NMDA receptor inhibition via a thiol oxygen sensor motif. Neuron 53:53–64
    [Google Scholar]
  152. 152. 
    Nakanishi N, Kang YJ, Tu S, McKercher SR, Masliah E, Lipton SA 2016. Differential effects of pharmacologic and genetic modulation of NMDA receptor activity on HIV/gp120-induced neuronal damage in an in vivo mouse model. J. Mol. Neurosci. 58:59–65
    [Google Scholar]
  153. 153. 
    Ghatak S, Dolatabadi N, Gao R, Wu Y, Scott H et al. 2020. NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models. Mol. Psychiatry https://doi.org/10.1038/s41380-020-0776-7
    [Crossref] [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-032320-015420
Loading
/content/journals/10.1146/annurev-pharmtox-032320-015420
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error