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Synaptic Dysfunction in Epilepsy

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Abstract

Epilepsy is one of the prevalent cerebral diseases, and despite intensive research of this pathology for many years, modern medicine cannot effectively control seizure manifestations in almost a third of patients. In epilepsy, there is a reorganization of neural networks, which is the result of the death of some neurons and the formation of new neuronal connections with altered properties. In this review, we focused on the analysis of changes in the properties of a key element of neural networks, the chemical synapse, immediately after epileptic activity, during epileptogenesis, and in chronic epilepsy. Since the synapse includes not only neuronal pre- and postsynaptic parts, but also glial components, our consideration includes changes in the properties of astrocytes and microglia. Epileptic activity causes numerous modifications in synapse function: changes in the probability of mediator release, the alteration of subunit composition of postsynaptic receptors, impairments of synaptic plasticity, and changes in morphology and activity of astrocytes and microglia. Glial cells release several gliatransmitters and cytokines, which in turn modify synaptic transmission. In some cases, the combination of these changes is favorable and allows compensating almost completely the consequences of epileptic activity for the nervous system. However, quite often, these changes, on the contrary, trigger a cascade of events leading to epilepsy and long-term disturbances in the functioning of neural networks. Over the past 10 years, significant progress has been achieved in deciphering these changes and their mechanisms, which is covered in our review. However, until now, researchers have not yet reached consensus on which particular modifications in the functioning of synapses provide optimal compensation and are able to prevent epileptogenesis. This knowledge could be the basis for the development of effective methods for epileptogenesis prevention and epilepsy treatment.

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REFERENCES

  1. Chin JH, Vora N (2014) The global burden of neurologic diseases. Neurology 83:349–351. https://doi.org/10.1212/WNL.0000000000000610

    Article  PubMed  PubMed Central  Google Scholar 

  2. Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, Resnick T, Benbadis SR (2014) The consequences of refractory epilepsy and its treatment. Epilepsy Behav 37:59–70. https://doi.org/10.1016/j.yebeh.2014.05.031

    Article  PubMed  Google Scholar 

  3. Pitkänen A, Lukasiuk K (2011) Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 10:173–186. https://doi.org/10.1016/S1474-4422(10)70310-0

    Article  PubMed  Google Scholar 

  4. Goldberg EM, Coulter DA (2013) Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction. Nat Rev Neurosci 14:337–349. https://doi.org/10.1038/nrn3482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ben-Ari Y (2008) Epilepsies and neuronal plasticity: for better or for worse? Dialogues Clin Neurosci 10:17–27. https://doi.org/10.31887/DCNS.2008.10.1/ybenari

    Article  PubMed  Google Scholar 

  6. Avoli M, Louvel J, Pumain R, Köhling R (2005) Cellular and molecular mechanisms of epilepsy in the human brain. Prog Neurobiol 77:166–200. https://doi.org/10.1016/j.pneurobio.2005.09.006

    Article  CAS  PubMed  Google Scholar 

  7. Epsztein J, Milh M, Bihi RI, Jorquera I, Ben-Ari Y, Represa A, Crépel V (2006) Ongoing epileptiform activity in the post-ischemic hippocampus is associated with a permanent shift of the excitatory-inhibitory synaptic balance in CA3 pyramidal neurons. J Neurosci 26:7082–7092. https://doi.org/10.1523/JNEUROSCI.1666-06.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Graebenitz S, Lesting J, Sosulina L, Seidenbecher T, Pape HC (2010) Alteration of NMDA receptor-mediated synaptic interactions in the lateral amygdala associated with seizure activity in a mouse model of chronic temporal lobe epilepsy. Epilepsia 51:1754–1762. https://doi.org/10.1111/j.1528-1167.2010.02561.x

    Article  CAS  PubMed  Google Scholar 

  9. Clarkson C, Smeal RM, Hasenoehrl MG, White JA, Rubio ME, Wilcox KS (2020) Ultrastructural and functional changes at the tripartite synapse during epileptogenesis in a model of temporal lobe epilepsy. Exp Neurol 326:113196. https://doi.org/10.1016/j.expneurol.2020.113196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yang J, Woodhall GL, Jones RSG (2006) Tonic facilitation of glutamate release by presynaptic NR2B-containing NMDA receptors is increased in the entorhinal cortex of chronically epileptic rats. J Neurosci 26:406–410. https://doi.org/10.1523/JNEUROSCI.4413-05.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Thompson SE, Ayman G, Woodhall GL, Jones RSG (2006) Depression of Glutamate and GABA Release by Presynaptic GABAB Receptors in the Entorhinal Cortex in Normal and Chronically Epileptic Rats. Neurosignals 15:202–215. https://doi.org/10.1159/000098515

    Article  CAS  PubMed  Google Scholar 

  12. Postnikova TY, Zubareva OE, Kovalenko AA, Kim KK, Magazanik LG, Zaitsev AV (2017) Status epilepticus impairs synaptic plasticity in rat hippocampus and is followed by changes in expression of NMDA receptors. Biochemistry (Moscow) 82:282–290. https://doi.org/10.1134/S0006297917030063

    Article  CAS  Google Scholar 

  13. Postnikova TY, Amakhin DV, Trofimova AM, Smolensky IV, Zaitsev AV (2019) Changes in Functional Properties of Rat Hippocampal Neurons Following Pentylenetetrazole-induced Status Epilepticus. Neuroscience 399:103–116. https://doi.org/10.1016/j.neuroscience.2018.12.029

    Article  CAS  PubMed  Google Scholar 

  14. Li S, Reinprecht I, Fahnestock M, Racine R (2002) Activity-dependent changes in synaptophysin immunoreactivity in hippocampus, piriform cortex, and entorhinal cortex of the rat. Neuroscience 115:1221–1229. https://doi.org/10.1016/S0306-4522(02)00485-2

    Article  CAS  PubMed  Google Scholar 

  15. Murthy VN, Sejnowski TJ, Stevens CF (1997) Heterogeneous release properties of visualized individual hippocampal synapses. Neuron 18:599–612. https://doi.org/10.1016/s0896-6273(00)80301-3

    Article  CAS  PubMed  Google Scholar 

  16. Upreti C, Otero R, Partida C, Skinner F, Thakker R, Pacheco LF, Zhou Z, Maglakelidze G, Velíšková J, Velíšek L, Romanovicz D, Jones T, Stanton PK, Garrido-Sanabria ER (2012) Altered neurotransmitter release, vesicle recycling and presynaptic structure in the pilocarpine model of temporal lobe epilepsy. Brain 135:869–885. https://doi.org/10.1093/brain/awr341

    Article  PubMed  PubMed Central  Google Scholar 

  17. Soussi R, Boulland JL, Bassot E, Bras H, Coulon P, Chaudhry FA, Storm-Mathisen J, Ferhat L, Esclapez M (2015) Reorganization of supramammillary–hippocampal pathways in the rat pilocarpine model of temporal lobe epilepsy: evidence for axon terminal sprouting. Brain Struct Funct 220:2449–2468. https://doi.org/10.1007/s00429-014-0800-2

    Article  PubMed  Google Scholar 

  18. Abegg MH, Savic N, Ehrengruber MU, McKinney RA, Gähwiler BH (2004) Epileptiform activity in rat hippocampus strengthens excitatory synapses. J Physiol 554:439–448. https://doi.org/10.1113/jphysiol.2003.052662

    Article  CAS  PubMed  Google Scholar 

  19. Debanne D, Thompson SM, Gähwiler BH (2006) A brief period of epileptiform activity strengthens excitatory synapses in the rat hippocampus in vitro. Epilepsia 47:247–256. https://doi.org/10.1111/j.1528-1167.2006.00416.x

    Article  PubMed  Google Scholar 

  20. Joshi S, Rajasekaran K, Sun H, Williamson J, Kapur J (2017) Enhanced AMPA receptor-mediated neurotransmission on CA1 pyramidal neurons during status epilepticus. Neurobiol Dis 103:45–53. https://doi.org/10.1016/j.nbd.2017.03.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rajasekaran K, Todorovic M, Kapur J (2012) Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus. Ann Neurol 72:91–102. https://doi.org/10.1002/ana.23570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Naylor DE, Liu H, Niquet J, Wasterlain CG (2013) Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus. Neurobiol Dis 54:225–238. https://doi.org/10.1016/j.nbd.2012.12.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wasterlain CG, Naylor DE, Liu H, Niquet J, Baldwin R (2013) Trafficking of NMDA receptors during status epilepticus: Therapeutic implications. Epilepsia 54:78–80. https://doi.org/10.1111/epi.12285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Amakhin DV, Soboleva EB, Ergina JL, Malkin SL, Chizhov AV, Zaitsev AV (2018) Seizure-Induced Potentiation of AMPA Receptor-Mediated Synaptic Transmission in the Entorhinal Cortex. Front Cell Neurosci 12:486. https://doi.org/10.3389/fncel.2018.00486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rajasekaran K, Joshi S, Kozhemyakin M, Todorovic MS, Kowalski S, Balint C, Kapur J (2013) Receptor trafficking hypothesis revisited: Plasticity of AMPA receptors during established status epilepticus. Epilepsia 54:14–16. https://doi.org/10.1111/epi.12266

    Article  PubMed  Google Scholar 

  26. Joshi S, Kapur J (2018) Mechanisms of status epilepticus: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor hypothesis. Epilepsia 59:71–81. https://doi.org/10.1111/epi.14482

    Article  CAS  Google Scholar 

  27. Doyon N, Vinay L, Prescott SA, De Koninck Y (2016) Chloride Regulation: A Dynamic Equilibrium Crucial for Synaptic Inhibition. Neuron 89:1157–1172. https://doi.org/10.1016/j.neuron.2016.02.030

    Article  CAS  PubMed  Google Scholar 

  28. Glykys J, Dzhala V, Egawa K, Balena T, Saponjian Y, Kuchibhotla KV, Bacskai BJ, Kahle KT, Zeuthen T, Staley KJ (2014) Local impermeant anions establish the neuronal chloride concentration. Science 343:670–675. https://doi.org/10.1126/science.1245423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Raimondo JV., Burman RJ, Katz AA, Akerman CJ (2015) Ion dynamics during seizures. Front Cell Neurosci 9:1–14. https://doi.org/10.3389/fncel.2015.00419

    Article  CAS  Google Scholar 

  30. Lillis KP, Kramer MA, Mertz J, Staley KJ, White JA (2012) Pyramidal cells accumulate chloride at seizure onset. Neurobiol Dis 47:358–366. https://doi.org/10.1016/j.nbd.2012.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fujiwara-Tsukamoto Y, Isomura Y, Nambu A, Takada M (2003) Excitatory GABA input directly drives seizure-like rhythmic synchronization in mature hippocampal CA1 pyramidal cells. Neuroscience 119:265–75. https://doi.org/10.1016/s0306-4522(03)00102-7

    Article  CAS  PubMed  Google Scholar 

  32. Librizzi L, Losi G, Marcon I, Sessolo M, Scalmani P, Carmignoto G, de Curtis M (2017) Interneuronal Network Activity at the Onset of Seizure-Like Events in Entorhinal Cortex Slices. J Neurosci 37:10398–10407. https://doi.org/10.1523/JNEUROSCI.3906-16.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Burman RJ, Selfe JS, Lee JH, van den Berg M, Calin A, Codadu NK, Wright R, Newey SE, Parrish RR, Katz AA, Wilmshurst JM, Akerman CJ, Trevelyan AJ, Raimondo J V. (2019) Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus. Brain 142:3482–3501. https://doi.org/10.1093/brain/awz283

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gibbs JW, Sombati S, Delorenzo RJ, Coulter DA (1997) Physiological and Pharmacological Alterations in Postsynaptic GABAA Receptor Function in a Hippocampal Culture Model of Chronic Spontaneous Seizures. J Neurophysiol 77:2139–2152. https://doi.org/10.1152/jn.1997.77.4.2139

    Article  CAS  PubMed  Google Scholar 

  35. Joshi S, Rajasekaran K, Hawk KM, Brar J, Ross BM, Tran CA, Chester SJ, Goodkin HP (2015) Phosphatase inhibition prevents the activity-dependent trafficking of GABAA receptors during status epilepticus in the young animal. Epilepsia 56:1355–1365. https://doi.org/10.1111/epi.13098

    Article  CAS  PubMed  Google Scholar 

  36. Goodkin HP, Joshi S, Mtchedlishvili Z, Brar J, Kapur J (2008) Subunit-specific trafficking of GABA(A) receptors during status epilepticus. J Neurosci 28:2527–2538. https://doi.org/10.1523/JNEUROSCI.3426-07.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Goodkin HP (2005) Status Epilepticus Increases the Intracellular Accumulation of GABAA Receptors. J Neurosci 25:5511–5520. https://doi.org/10.1523/JNEUROSCI.0900-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Erreger K, Geballe MT, Kristensen A, Chen PE, Hansen KB, Lee CJ, Yuan H, Le P, Lyuboslavsky PN, Micale N, Jørgensen L, Clausen RP, Wyllie DJA, Snyder JP, Traynelis SF (2007) Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors. Mol Pharmacol 72:907–920. https://doi.org/10.1124/mol.107.037333

    Article  CAS  PubMed  Google Scholar 

  39. Chen Q, He S, Hu XL, Yu J, Zhou Y, Zheng J, Zhang S, Zhang C, Duan WH, Xiong ZQ (2007) Differential roles of NR2A- and NR2B-containing NMDA receptors in activity-dependent brain-derived neurotrophic factor gene regulation and limbic epileptogenesis. J Neurosci 27:542–552. https://doi.org/10.1523/JNEUROSCI.3607-06.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Amakhin DV, Malkin SL, Ergina JL, Kryukov KA, Veniaminova EA, Zubareva OE, Zaitsev AV (2017) Alterations in Properties of Glutamatergic Transmission in the Temporal Cortex and Hippocampus Following Pilocarpine-Induced Acute Seizures in Wistar Rats. Front Cell Neurosci 11:264. https://doi.org/10.3389/fncel.2017.00264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Di Maio R, Mastroberardino PG, Hu X, Montero L, Greenamyre JT (2011) Pilocapine alters NMDA receptor expression and function in hippocampal neurons: NADPH oxidase and ERK1/2 mechanisms. Neurobiol Dis 42:482–495. https://doi.org/10.1016/j.nbd.2011.02.012

    Article  CAS  PubMed  Google Scholar 

  42. Di Maio R, Mastroberardino PG, Hu X, Montero LM, Greenamyre JT (2013) Thiol oxidation and altered NR2B/NMDA receptor functions in in vitro and in vivo pilocarpine models: Implications for epileptogenesis. Neurobiol Dis 49:87–98. https://doi.org/10.1016/j.nbd.2012.07.013

    Article  CAS  PubMed  Google Scholar 

  43. Zhu X, Dong J, Shen K, Bai Y, Zhang Y, Lv X, Chao J, Yao H (2015) NMDA receptor NR2B subunits contribute to PTZ-kindling-induced hippocampal astrocytosis and oxidative stress. Brain Res Bull 114:70–78. https://doi.org/10.1016/j.brainresbull.2015.04.002

    Article  CAS  PubMed  Google Scholar 

  44. Chen B, Feng B, Tang Y, You Y, Wang Y, Hou W, Hu W, Chen Z (2016) Blocking GluN2B subunits reverses the enhanced seizure susceptibility after prolonged febrile seizures with a wide therapeutic time-window. Exp Neurol 283:29–38. https://doi.org/10.1016/j.expneurol.2016.05.034

    Article  CAS  PubMed  Google Scholar 

  45. Frasca A, Aalbers M, Frigerio F, Fiordaliso F, Salio M, Gobbi M, Cagnotto A, Gardoni F, Battaglia GS, Hoogland G, Di Luca M, Vezzani A (2011) Misplaced NMDA receptors in epileptogenesis contribute to excitotoxicity. Neurobiol Dis 43:507–515. https://doi.org/10.1016/j.nbd.2011.04.024

    Article  CAS  PubMed  Google Scholar 

  46. Isaac JTR, Ashby MC, McBain CJ (2007) The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron 54:859–871. https://doi.org/10.1016/j.neuron.2007.06.001

    Article  CAS  PubMed  Google Scholar 

  47. Geiger JRP, Melcher T, Koh DS, Sakmann B, Seeburg PH, Jonas P, Monyer H (1995) Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS. Neuron 15:193–204. https://doi.org/10.1016/0896-6273(95)90076-4

    Article  CAS  PubMed  Google Scholar 

  48. Kumar SS, Bacci A, Kharazia V, Huguenard JR (2002) A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons. J Neurosci 22:3005–3015. https://doi.org/10.1523/jneurosci.22-08-03005.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Henley JM, Wilkinson KA (2016) Synaptic AMPA receptor composition in development, plasticity and disease. Nat Rev Neurosci 17:337–350. https://doi.org/10.1038/nrn.2016.37

    Article  CAS  PubMed  Google Scholar 

  50. Grooms SY (2000) Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death. Proc Natl Acad Sci 97:3631–3636. https://doi.org/10.1073/pnas.050586497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sommer C, Roth SU, Kiessling M (2001) Kainate-induced epilepsy alters protein expression of AMPA receptor subunits GluR1, GluR2 and AMPA receptor binding protein in the rat hippocampus. Acta Neuropathol 101:460–468. https://doi.org/10.1007/s004010000310

    Article  CAS  PubMed  Google Scholar 

  52. Sanchez RM, Koh S, Rio C, Wang C, Lamperti ED, Sharma D, Corfas G, Jensen FE (2001) Decreased glutamate receptor 2 expression and enhanced epileptogenesis in immature rat hippocampus after perinatal hypoxia-induced seizures. J Neurosci 21:8154–8163. https://doi.org/10.1523/jneurosci.21-20-08154.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Friedman LK (1998) Selective reduction of GluR2 protein in adult hippocampal CA3 neurons following status epilepticus but prior to cell loss. Hippocampus 8:511–525. https://doi.org/10.1002/(SICI)1098-1063(1998)8:5<511::AID-HIPO9>3.0.CO;2-W

    Article  CAS  PubMed  Google Scholar 

  54. Malkin SL, Amakhin DV, Veniaminova EA, Kim KK, Zubareva OE, Magazanik LG, Zaitsev AV (2016) Changes of ampa receptor properties in the neocortex and hippocampus following pilocarpine-induced status epilepticus in rats. Neuroscience 327:146–155. https://doi.org/10.1016/j.neuroscience.2016.04.024

    Article  CAS  PubMed  Google Scholar 

  55. Pellegrini-Giampietro DE, Gorter JA, Bennett MVL, Zukin RS (1997) The GluR2 (GluR‑B) hypothesis: Ca2+-permeable AMPA receptors in neurological disorders. Trends Neurosci 20:464–470. https://doi.org/10.1016/S0166-2236(97)01100-4

    Article  CAS  PubMed  Google Scholar 

  56. Hu Y, Jiang L, Chen H, Zhang XP (2012) Expression of AMPA receptor subunits in hippocampus after status convulsion. Child’s Nerv Syst 28:911–918. https://doi.org/10.1007/s00381-012-1747-3

    Article  Google Scholar 

  57. Russo I, Bonini D, Via LLa, Barlati S, Barbon A (2013) AMPA receptor properties are modulated in the early stages following pilocarpine-induced status epilepticus. Neuromol Med 15:324–338. https://doi.org/10.1007/s12017-013-8221-6

    Article  CAS  Google Scholar 

  58. Zaitsev AV, Kim KK, Frolova EV, Lavrent’eva VV, Lukomskaya NY, Magazanik LG (2014) Anticonvulsant activities of antagonists of NMDA and calcium-permeable AMPA receptors in a model of maximum electroshock in rats. Neurochem J 8:301–305. https://doi.org/10.1134/S1819712414040138

    Article  CAS  Google Scholar 

  59. Szczurowska E, Mares P (2015) An antagonist of calcium permeable AMPA receptors, IEM1460: Anticonvulsant action in immature rats? Epilepsy Res 109:106–113. https://doi.org/10.1016/j.eplepsyres.2014.10.020

    Article  CAS  PubMed  Google Scholar 

  60. Szczurowska E, Mareš P (2013) NMDA and AMPA receptors: Development and status epilepticus. Physiol Res 62:21–38. https://doi.org/10.33549/physiolres.932662

    Article  Google Scholar 

  61. Konen LM, Wright AL, Royle GA, Morris GP, Lau BK, Seow PW, Zinn R, Milham LT, Vaughan CW, Vissel B (2020) A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability. Mol Brain 13:27. https://doi.org/10.1186/s13041-020-0545-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rakhade SN, Zhou C, Aujla PK, Fishman R, Sucher NJ, Jensen FE (2008) Early Alterations of AMPA Receptors Mediate Synaptic Potentiation Induced by Neonatal Seizures. J Neurosci 28:7979–7990. https://doi.org/10.1523/JNEUROSCI.1734-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lippman-Bell JJ, Rakhade SN, Klein PM, Obeid M, Jackson MC, Joseph A, Jensen FE (2013) AMPA Receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures. Epilepsia 54:1922–1932. https://doi.org/10.1111/epi.12378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Krestel HE, Shimshek DR, Jensen V, Nevian T, Kim J, Geng Y, Bast T, Depaulis A, Schonig K, Schwenk F, Bujard H, Hvalby Ø, Sprengel R, Seeburg PH (2004) A Genetic Switch for Epilepsy in Adult Mice. J Neurosci 24:10568–10578. https://doi.org/10.1523/JNEUROSCI.4579-03.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Brusa R, Zimmermann F, Koh D-S, Feldmeyer D, Gass P, Seeburg PH, Sprengel R (1995) Early-Onset Epilepsy and Postnatal Lethality Associated with an Editing-Deficient GluR-B Allele in Mice. Science 270:1677–1680. https://doi.org/10.1126/science.270.5242.1677

    Article  CAS  PubMed  Google Scholar 

  66. Lorgen J-Ø, Egbenya DL, Hammer J, Davanger S (2017) PICK1 facilitates lasting reduction in GluA2 concentration in the hippocampus during chronic epilepsy. Epilepsy Res 137:25–32. https://doi.org/10.1016/j.eplepsyres.2017.08.012

    Article  CAS  PubMed  Google Scholar 

  67. Pirker S, Schwarzer C, Czech T, Baumgartner C, Pockberger H, Maier H, Hauer B, Sieghart W, Furtinger S, Sperk G (2003) Increased Expression of GABA A Receptor β-Subunits in the Hippocampus of Patients with Temporal Lobe Epilepsy. J Neuropathol Exp Neurol 62:820–834. https://doi.org/10.1093/jnen/62.8.820

    Article  CAS  PubMed  Google Scholar 

  68. Loup F, Wieser H-G, Yonekawa Y, Aguzzi A, Fritschy J-M (2000) Selective Alterations in GABA A Receptor Subtypes in Human Temporal Lobe Epilepsy. J Neurosci 20:5401–5419. https://doi.org/10.1523/JNEUROSCI.20-14-05401.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Loddenkemper T, Talos DM, Cleary RT, Joseph A, Sánchez Fernández I, Alexopoulos A, Kotagal P, Najm I, Jensen FE (2014) Subunit composition of glutamate and gamma-aminobutyric acid receptors in status epilepticus. Epilepsy Res 108:605–615. https://doi.org/10.1016/j.eplepsyres.2014.01.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mathern GW, Pretorius JK, Kornblum HI, Mendoza D, Lozada A, Leite JP, Chimelli LMC, Fried I, Sakamoto AC, Assirati JA, Lévesque MF, Adelson PD, Peacock WJ (1997) Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients. Brain 120:1937–1959. https://doi.org/10.1093/brain/120.11.1937

    Article  PubMed  Google Scholar 

  71. Talos DM, Kwiatkowski DJ, Cordero K, Black PM, Jensen FE (2008) Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers. Ann Neurol 63:454–465. https://doi.org/10.1002/ana.21342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sánchez Fernández I, Loddenkemper T (2014) Subunit Composition of Neurotransmitter Receptors in the Immature and in the Epileptic Brain. Biomed Res Int 2014:1–11. https://doi.org/10.1155/2014/301950

    Article  CAS  Google Scholar 

  73. Möddel G, Jacobson B, Ying Z, Janigro D, Bingaman W, González-Martínez J, Kellinghaus C, Prayson RA, Najm IM (2005) The NMDA receptor NR2B subunit contributes to epileptogenesis in human cortical dysplasia. Brain Res 1046:10–23. https://doi.org/10.1016/j.brainres.2005.03.042

    Article  CAS  PubMed  Google Scholar 

  74. Klatte K, Kirschstein T, Otte D, Pothmann L, Müller L, Tokay T, Kober M, Uebachs M, Zimmer A, Beck H (2013) Impaired D-serine-mediated cotransmission mediates cognitive dysfunction in epilepsy. J Neurosci 33:13066–13080. https://doi.org/10.1523/JNEUROSCI.5423-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Egbenya DL, Hussain S, Lai Y-C, Xia J, Anderson AE, Davanger S (2018) Changes in synaptic AMPA receptor concentration and composition in chronic temporal lobe epilepsy. Mol Cell Neurosci 92:93–103. https://doi.org/10.1016/j.mcn.2018.07.004

    Article  CAS  PubMed  Google Scholar 

  76. Kitaura H, Sonoda M, Teramoto S, Shirozu H, Shimizu H, Kimura T, Masuda H, Ito Y, Takahashi H, Kwak S, Kameyama S, Kakita A (2017) Ca2+-permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma. Epilepsia 58:e59–e63. https://doi.org/10.1111/epi.13700

    Article  CAS  PubMed  Google Scholar 

  77. Prince HC, Tzingounis AV, Levey AI, Conn PJ (2000) Functional downregulation of GluR2 in piriform cortex of kindled animals. Synapse 38:489–498. https://doi.org/10.1002/1098-2396(20001215)38:4<489::AID-SYN15>3.0.CO;2-N

    Article  CAS  PubMed  Google Scholar 

  78. Brooks-Kayal AR, Pritchett DB (1993) Developmental changes in human gamma-aminobutyric acidA receptor subunit composition. Ann Neurol 34:687–693. https://doi.org/10.1002/ana.410340511

    Article  CAS  PubMed  Google Scholar 

  79. Poulter MO, Brown LA, Tynan S, Willick G, William R, McIntyre DC (1999) Differential Expression of α1, α2, α3, and α5 GABAA Receptor Subunits in Seizure-Prone and Seizure-Resistant Rat Models of Temporal Lobe Epilepsy. J Neurosci 19:4654–4661. https://doi.org/10.1523/JNEUROSCI.19-11-04654.1999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Galanopoulou AS, Moshé SL (2014) Does Epilepsy Cause a Reversion to Immature Function? Adv Exp Med Biol 813:195–209. https://doi.org/10.1007/978-94-017-8914-1_16

    Article  PubMed  PubMed Central  Google Scholar 

  81. Citri A, Malenka RC (2008) Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms. Neuropsychopharmacology 33:18–41. https://doi.org/10.1038/sj.npp.1301559

    Article  PubMed  Google Scholar 

  82. Lepeta K, Lourenco MV, Schweitzer BC, Martino Adami PV, Banerjee P, Catuara‑Solarz S, de La Fuente Revenga M, Guillem AM, Haidar M, Ijomone OM, Nadorp B, Qi L, Perera ND, Refsgaard LK, Reid KM, Sabbar M, Sahoo A, Schaefer N, Sheean RK, Suska A, Verma R, Vicidomini C, Wright D, Zhang X-D, Seidenbecher C (2016) Synaptopathies: synaptic dysfunction in neurological disorders—A review from students to students. J Neurochem 138:785–805. https://doi.org/10.1111/jnc.13713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bliss TVP, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39. https://doi.org/10.1038/361031a0

    Article  CAS  PubMed  Google Scholar 

  84. Neves G, Cooke SF, Bliss TVP (2008) Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci 9:65–75. https://doi.org/10.1038/nrn2303

    Article  CAS  PubMed  Google Scholar 

  85. Brown TH, Chapman PF, Kairiss EW, Keenan CL (1988) Long-term synaptic potentiation. Science 242:724–728. https://doi.org/10.1126/science.2903551

    Article  CAS  PubMed  Google Scholar 

  86. Shah P, Bassett DS, Wisse LEM, Detre JA, Stein JM, Yushkevich PA, Shinohara RT, Pluta JB, Valenciano E, Daffner M, Wolk DA, Elliott MA, Litt B, Davis KA, Das SR (2018) Mapping the structural and functional network architecture of the medial temporal lobe using 7T MRI. Hum Brain Mapp 39:851–865. https://doi.org/10.1002/hbm.23887

    Article  PubMed  Google Scholar 

  87. Mathern GW, Adelson PD, Cahan LD, Leite JP (2002) Hippocampal neuron damage in human epilepsy: Meyer’s hypothesis revisited. Prog Brain Res 135:237–51. https://doi.org/10.1016/s0079-6123(02)35023-4

    Article  PubMed  Google Scholar 

  88. Postnikova TY, Amakhin DV, Trofimova AM, Zaitsev AV (2020) Calcium-permeable AMPA receptors are essential to the synaptic plasticity induced by epileptiform activity in rat hippocampal slices. Biochem Biophys Res Commun 529:1145–1150. https://doi.org/10.1016/j.bbrc.2020.06.121

    Article  CAS  PubMed  Google Scholar 

  89. Plant K, Pelkey KA, Bortolotto ZA, Morita D, Terashima A, McBain CJ, Collingridge GL, Isaac JTR (2006) Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation. Nat Neurosci 9:602–604. https://doi.org/10.1038/nn1678

    Article  CAS  PubMed  Google Scholar 

  90. Zhou J-L, Shatskikh TN, Liu X, Holmes GL (2007) Impaired single cell firing and long-term potentiation parallels memory impairment following recurrent seizures. Eur J Neurosci 25:3667–77. https://doi.org/10.1111/j.1460-9568.2007.05598.x

    Article  PubMed  Google Scholar 

  91. Suárez LM, Cid E, Gal B, Inostroza M, Brotons-Mas JR, Gómez-Domínguez D, de la Prida LM, Solís JM (2012) Systemic Injection of Kainic Acid Differently Affects LTP Magnitude Depending on its Epileptogenic Efficiency. PLoS One 7:e48128. https://doi.org/10.1371/journal.pone.0048128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cunha AOS, de Oliveira JAC, Almeida SS, Garcia-Cairasco N, Leão RM (2015) Inhibition of long-term potentiation in the schaffer-CA1 pathway by repetitive high-intensity sound stimulation. Neuroscience 310:114–127. https://doi.org/10.1016/j.neuroscience.2015.09.040

    Article  CAS  PubMed  Google Scholar 

  93. Kryukov KA, Kim KK, Magazanik LG, Zaitsev AV (2016) Status epilepticus alters hippocampal long-term synaptic potentiation in a rat lithium-pilocarpine model. Neuroreport 27:1191–1195. https://doi.org/10.1097/WNR.0000000000000656

    Article  CAS  PubMed  Google Scholar 

  94. Plata A, Lebedeva A, Denisov P, Nosova O, Postnikova TY, Pimashkin A, Brazhe A, Zaitsev AV, Rusakov DA, Semyanov A (2018) Astrocytic Atrophy Following Status Epilepticus Parallels Reduced Ca2+ Activity and Impaired Synaptic Plasticity in the Rat Hippocampus. Front Mol Neurosci 11:215. https://doi.org/10.3389/fnmol.2018.00215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Postnikova TY, Trofimova AM, Ergina JL, Zubareva OE, Kalemenev SV, Zaitsev AV (2019) Transient Switching of NMDA-Dependent Long-Term Synaptic Potentiation in CA3-CA1 Hippocampal Synapses to mGluR1-Dependent Potentiation After Pentylenetetrazole-Induced Acute Seizures in Young Rats. Cell Mol Neurobiol 39:287–300. https://doi.org/10.1007/s10571-018-00647-3

    Article  CAS  PubMed  Google Scholar 

  96. Guli X, Tokay T, Kirschstein T, Köhling R (2016) Status Epilepticus Enhances Depotentiation after Fully Established LTP in an NMDAR-Dependent but GluN2B-Independent Manner. Neural Plast 2016:6592038. https://doi.org/10.1155/2016/6592038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. O’Leary H, Bernard PB, Castano AM, Benke TA (2016) Enhanced long term potentiation and decreased AMPA receptor desensitization in the acute period following a single kainate induced early life seizure. Neurobiol Dis 87:134–144. https://doi.org/10.1016/j.nbd.2015.12.005

    Article  CAS  PubMed  Google Scholar 

  98. Müller L, Tokay T, Porath K, Köhling R, Kirschstein T (2013) Enhanced NMDA receptor-dependent LTP in the epileptic CA1 area via upregulation of NR2B. Neurobiol Dis 54:183–193. https://doi.org/10.1016/j.nbd.2012.12.011

    Article  CAS  PubMed  Google Scholar 

  99. Ivanov AD, Zaitsev AV (2017) NMDAR-independent hippocampal long-term depression impairment after status epilepticus in a lithium-pilocarpine model of temporal lobe epilepsy. Synapse 71:e21982. https://doi.org/10.1002/syn.21982

    Article  CAS  Google Scholar 

  100. Barria A, Malinow R (2005) NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron 48:289–301. https://doi.org/10.1016/j.neuron.2005.08.034

    Article  CAS  PubMed  Google Scholar 

  101. Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14:383–400. https://doi.org/10.1038/nrn3504

    Article  CAS  PubMed  Google Scholar 

  102. Parsons MP, Raymond LA (2014) Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron 82:279–93. https://doi.org/10.1016/j.neuron.2014.03.030

    Article  CAS  PubMed  Google Scholar 

  103. Franchini L, Carrano N, Di Luca M, Gardoni F (2020) Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity. Int J Mol Sci 21:1538. https://doi.org/10.3390/ijms21041538

    Article  CAS  PubMed Central  Google Scholar 

  104. Li R, Huang FS, Abbas AK, Wigström H (2007) Role of NMDA receptor subtypes in different forms of NMDA-dependent synaptic plasticity. BMC Neurosci 8:55. https://doi.org/10.1186/1471-2202-8-55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Liu L, Wong TP, Pozza MF, Lingenhoehl K, Wang YT, Sheng M, Auberson YP, Wang YT (2004) Role of NMDA Receptor Subtypes in Governing the Direction of Hippocampal Synaptic Plasticity. Science 304:1021–1024. https://doi.org/10.1126/science.1096615

    Article  CAS  PubMed  Google Scholar 

  106. Massey PV, Johnson BE, Moult PR, Auberson YP, Brown MW, Molnar E, Collingridge GL, Bashir ZI (2004) Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci 24:7821–7828. https://doi.org/10.1523/JNEUROSCI.1697-04.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bartlett TE, Bannister NJ, Collett VJ, Dargan SL, Massey PV, Bortolotto ZA, Fitzjohn SM, Bashir ZI, Collingridge GL, Lodge D (2007) Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus. Neuropharmacology 52:60–70. https://doi.org/10.1016/j.neuropharm.2006.07.013

    Article  CAS  PubMed  Google Scholar 

  108. Xu Z, Chen RQ, Gu QH, Yan JZ, Wang SH, Liu SY, Lu W (2009) Metaplastic regulation of long-term potentiation/long-term depression threshold by activity-dependent changes of NR2A/NR2B ratio. J Neurosci 29:8764–8773. https://doi.org/10.1523/JNEUROSCI.1014-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Fox CJ, Russell KI, Wang YT, Christie BR (2006) Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo. Hippocampus 16:907–915. https://doi.org/10.1002/hipo.20230

    Article  CAS  PubMed  Google Scholar 

  110. Scheefhals N, MacGillavry HD (2018) Functional organization of postsynaptic glutamate receptors. Mol Cell Neurosci 91:82–94. https://doi.org/10.1016/j.mcn.2018.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Anwyl R (2009) Metabotropic glutamate receptor-dependent long-term potentiation. Neuropharmacology 56:735–740. https://doi.org/10.1016/j.neuropharm.2009.01.002

    Article  CAS  PubMed  Google Scholar 

  112. O’neill N, McLaughlin C, Komiyama N, Sylantyev S (2018) Biphasic modulation of NMDA receptor function by metabotropic glutamate receptors. J Neurosci 38:9840–9855. https://doi.org/10.1523/JNEUROSCI.1000-18.2018

    Article  PubMed  PubMed Central  Google Scholar 

  113. Lai TKY, Zhai D, Su P, Jiang A, Boychuk J, Liu F (2019) The receptor-receptor interaction between mGluR1 receptor and NMDA receptor: a potential therapeutic target for protection against ischemic stroke. FASEB J 33:14423–14439. https://doi.org/10.1096/fj.201900417R

    Article  CAS  PubMed  Google Scholar 

  114. Merlin LR, Wong RKS (1997) Role of group I metabotropic glutamate receptors in the patterning of epileptiform activities in vitro. J Neurophysiol 78:539–544. https://doi.org/10.1152/jn.1997.78.1.539

    Article  CAS  PubMed  Google Scholar 

  115. Lapointe V, Morin F, Ratté S, Croce A, Conquet F, Lacaille JC (2004) Synapse-specific mGluR1-dependent long-term potentiation in interneurones regulates mouse hippocampal inhibition. J Physiol 555:125–135. https://doi.org/10.1113/jphysiol.2003.053603

    Article  CAS  PubMed  Google Scholar 

  116. Perez Y, Morin F, Lacaille JC (2001) A hebbian form of long-term potentiation dependent on mGluR1a in hippocampal inhibitory interneurons. Proc Natl Acad Sci U S A 98:9401–9406. https://doi.org/10.1073/pnas.161493498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Akbar MT, Rattray M, Powell JF, Meldrum BS (1996) Altered expression of group I metabotropic glutamate receptors in the hippocampus of amygdala-kindled rats. Mol Brain Res 43:105–116. https://doi.org/10.1016/S0169-328X(96)00162-3

    Article  CAS  PubMed  Google Scholar 

  118. Blümcke I, Suter B, Behle K, Kuhn R, Schramm J, Elger CE, Wiestler OD (2000) Loss of hilar mossy cells in Ammon’s horn sclerosis. Epilepsia 41 Suppl 6:S174-180. https://doi.org/10.1111/j.1528-1157.2000.tb01577.x

    Article  Google Scholar 

  119. Vizuete AFK, Hansen F, Negri E, Leite MC, de Oliveira DL, Gonçalves C-A (2018) Effects of dexamethasone on the Li-pilocarpine model of epilepsy: protection against hippocampal inflammation and astrogliosis. J Neuroinflam 15:68. https://doi.org/10.1186/s12974-018-1109-5

    Article  CAS  Google Scholar 

  120. Stogsdill JA, Eroglu C (2017) The interplay between neurons and glia in synapse development and plasticity. Curr Opin Neurobiol 42:1–8. https://doi.org/10.1016/j.conb.2016.09.016

    Article  CAS  PubMed  Google Scholar 

  121. Patel DC, Tewari BP, Chaunsali L, Sontheimer H (2019) Neuron–glia interactions in the pathophysiology of epilepsy. Nat Rev Neurosci 20:282–297. https://doi.org/10.1038/s41583-019-0126-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Croft W, Dobson KL, Bellamy TC (2015) Plasticity of Neuron-Glial Transmission: Equipping Glia for Long-Term Integration of Network Activity. Neural Plast 2015:765792. https://doi.org/10.1155/2015/765792

    Article  PubMed  PubMed Central  Google Scholar 

  123. Hol EM, Pekny M (2015) Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr Opin Cell Biol 32:121–130. https://doi.org/10.1016/j.ceb.2015.02.004

    Article  CAS  PubMed  Google Scholar 

  124. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. https://doi.org/10.1007/s00401-009-0619-8

    Article  PubMed  Google Scholar 

  125. Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565:30–38. https://doi.org/10.1016/j.neulet.2013.12.071

    Article  CAS  PubMed  Google Scholar 

  126. Kandratavicius L, Peixoto-Santos JE, Monteiro MR, Scandiuzzi RC, Carlotti CG, Assirati JA, Hallak JE, Leite JP (2015) Mesial temporal lobe epilepsy with psychiatric comorbidities: A place for differential neuroinflammatory interplay. J Neuroinflam 12:1–12. https://doi.org/10.1186/s12974-015-0266-z

    Article  Google Scholar 

  127. Hubbard JA, Szu JI, Yonan JM, Binder DK (2016) Regulation of astrocyte glutamate transporter-1 (GLT1) and aquaporin-4 (AQP4) expression in a model of epilepsy. Exp Neurol 283:85–96. https://doi.org/10.1016/j.expneurol.2016.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Rossi AR, Angelo MF, Villarreal A, Lukin J, Ramos AJ (2013) Gabapentin Administration Reduces Reactive Gliosis and Neurodegeneration after Pilocarpine-Induced Status Epilepticus. PLoS One 8:e78516. https://doi.org/10.1371/journal.pone.0078516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Steinhäuser C, Grunnet M, Carmignoto G (2016) Crucial role of astrocytes in temporal lobe epilepsy. Neuroscience 323:157–169. https://doi.org/10.1016/j.neuroscience.2014.12.047

    Article  CAS  PubMed  Google Scholar 

  130. Zaitsev AV, Smolensky IV, Jorratt P, Ovsepian SV (2020) Neurobiology, Functions, and Relevance of Excitatory AminoAcid Transporters (EAATs) to Treatment of Refractory Epilepsy. CNS Drugs 34:1089–1103. https://doi.org/10.1007/s40263-020-00764-y

    Article  CAS  PubMed  Google Scholar 

  131. Boison D, Steinhäuser C (2018) Epilepsy and astrocyte energy metabolism. Glia 66:1235–1243. https://doi.org/10.1002/glia.23247

    Article  PubMed  Google Scholar 

  132. Kong Q, Takahashi K, Schulte D, Stouffer N, Lin Y, Lin C-LG (2012) Increased glial glutamate transporter EAAT2 expression reduces epileptogenic processes following pilocarpine-induced status epilepticus. Neurobiol Dis 47:145–154. https://doi.org/10.1016/j.nbd.2012.03.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Heuser K, Nome CG, Pettersen KH, Åbjørsbråten KS, Jensen V, Tang W, Sprengel R, Taubøll E, Nagelhus EA, Enger R (2018) Ca2+ Signals in Astrocytes Facilitate Spread of Epileptiform Activity. Cereb Cortex 28:4036–4048. https://doi.org/10.1093/cercor/bhy196

    Article  PubMed  PubMed Central  Google Scholar 

  134. Ding S, Fellin T, Zhu Y, Lee S-Y, Auberson YP, Meaney DF, Coulter DA, Carmignoto G, Haydon PG (2007) Enhanced Astrocytic Ca2+ Signals Contribute to Neuronal Excitotoxicity after Status Epilepticus. J Neurosci 27:10674–10684. https://doi.org/10.1523/JNEUROSCI.2001-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wetherington J, Serrano G, Dingledine R (2008) Astrocytes in the Epileptic Brain. Neuron

    Book  Google Scholar 

  136. Eilert-Olsen M, Hjukse JB, Thoren AE, Tang W, Enger R, Jensen V, Pettersen KH, Nagelhus EA (2019) Astroglial endfeet exhibit distinct Ca2+ signals during hypoosmotic conditions. Glia 67:2399–2409. https://doi.org/10.1002/glia.23692

    Article  PubMed  Google Scholar 

  137. Petravicz J, Boyt KM, McCarthy KD (2014) Astrocyte IP3R2-dependent Ca2+ signaling is not a major modulator of neuronal pathways governing behavior. Front Behav Neurosci 8:384. https://doi.org/10.3389/fnbeh.2014.00384

    Article  PubMed  PubMed Central  Google Scholar 

  138. Bazan NG (2012) Neuroinflammation and proteostasis are modulated by endogenously biosynthesized neuroprotectin D1. Mol Neurobiol 46:221–226. https://doi.org/10.1007/s12035-012-8322-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Skaper SD (2007) The brain as a target for inflammatory processes and neuroprotective strategies. Ann N Y Acad Sci 1122:23–34. https://doi.org/10.1196/annals.1403.002

    Article  CAS  PubMed  Google Scholar 

  140. Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA (2013) Glia and epilepsy: excitability and inflammation. Trends Neurosci 36:174–184. https://doi.org/10.1016/j.tins.2012.11.008

    Article  CAS  PubMed  Google Scholar 

  141. Hiragi T, Ikegaya Y, Koyama R (2018) Microglia after Seizures and in Epilepsy. Cells 7:26. https://doi.org/10.3390/cells7040026

    Article  CAS  PubMed Central  Google Scholar 

  142. Kagitani-Shimono K, Kato H, Kuwayama R, Tominaga K, Nabatame S, Kishima H, Hatazawa J, Taniike M (2021) Clinical evaluation of neuroinflammation in child-onset focal epilepsy: a translocator protein PET study. J Neuroinflam 18:8. https://doi.org/10.1186/s12974-020-02055-1

    Article  CAS  Google Scholar 

  143. Kinoshita S, Koyama R (2021) Pro- and anti-epileptic roles of microglia. Neural Regen Res 16:1369. https://doi.org/10.4103/1673-5374.300976

    Article  PubMed  Google Scholar 

  144. Eyo UB, Peng J, Swiatkowski P, Mukherjee A, Bispo A, Wu L-J (2014) Neuronal Hyperactivity Recruits Microglial Processes via Neuronal NMDA Receptors and Microglial P2Y12 Receptors after Status Epilepticus. J Neurosci 34:10528–10540. https://doi.org/10.1523/JNEUROSCI.0416-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kumaria A, Tolias CM, Burnstock G (2008) ATP signalling in epilepsy. Purinergic Signal 4:339–346. https://doi.org/10.1007/s11302-008-9115-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Morin-Brureau M, Milior G, Royer J, Chali F, Le Duigou C, Savary E, Blugeon C, Jourdren L, Akbar D, Dupont S, Navarro V, Baulac M, Bielle F, Mathon B, Clemenceau S, Miles R (2018) Microglial phenotypes in the human epileptic temporal lobe. Brain 141:3343–3360. https://doi.org/10.1093/brain/awy276

    Article  PubMed  Google Scholar 

  147. Ransohoff RM (2009) Chemokines and Chemokine Receptors: Standing at the Crossroads of Immunobiology and Neurobiology. Immunity 31:711–721. https://doi.org/10.1016/j.immuni.2009.09.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Yeo S-I, Kim J-E, Ryu HJ, Seo CH, Lee BC, Choi I-G, Kim D-S, Kang T-C (2011) The roles of fractalkine/CX3CR1 system in neuronal death following pilocarpine-induced status epilepticus. J Neuroimmunol 234:93–102. https://doi.org/10.1016/j.jneuroim.2011.03.005

    Article  CAS  PubMed  Google Scholar 

  149. Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, Ishii M, Yamashita T (2013) Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci 16:543–551. https://doi.org/10.1038/nn.3358

    Article  CAS  PubMed  Google Scholar 

  150. Rappold PM, Lynd-Balta E, Joseph SA (2006) P2X7 receptor immunoreactive profile confined to resting and activated microglia in the epileptic brain. Brain Res 1089:171–178. https://doi.org/10.1016/j.brainres.2006.03.040

    Article  CAS  PubMed  Google Scholar 

  151. Jimenez-Pacheco A, Diaz-Hernandez M, Arribas-Blázquez M, Sanz-Rodriguez A, Olivos-Oré LA, Artalejo AR, Alves M, Letavic M, Miras-Portugal MT, Conroy RM, Delanty N, Farrell MA, O’Brien DF, Bhattacharya A, Engel T, Henshall DC (2016) Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy. J Neurosci 36:5920–5932. https://doi.org/10.1523/JNEUROSCI.4009-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Kim J-E, Kang T-C (2011) The P2X7 receptor–pannexin-1 complex decreases muscarinic acetylcholine receptor–mediated seizure susceptibility in mice. J Clin Invest 121:2037–2047. https://doi.org/10.1172/JCI44818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Raghunatha P, Vosoughi A, Kauppinen TM, Jackson MF (2020) Microglial NMDA receptors drive pro-inflammatory responses via PARP-1/TRMP2 signaling. Glia 68:1421–1434. https://doi.org/10.1002/glia.23790

    Article  PubMed  Google Scholar 

  154. Matsuda T, Murao N, Katano Y, Juliandi B, Kohyama J, Akira S, Kawai T, Nakashima K (2015) TLR9 signalling in microglia attenuates seizure-induced aberrant neurogenesis in the adult hippocampus. Nat Commun 6:6514. https://doi.org/10.1038/ncomms7514

    Article  CAS  PubMed  Google Scholar 

  155. Klement W, Garbelli R, Zub E, Rossini L, Tassi L, Girard B, Blaquiere M, Bertaso F, Perroy J, de Bock F, Marchi N (2018) Seizure progression and inflammatory mediators promote pericytosis and pericyte-microglia clustering at the cerebrovasculature. Neurobiol Dis 113:70–81. https://doi.org/10.1016/j.nbd.2018.02.002

    Article  CAS  PubMed  Google Scholar 

  156. Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R, Sonobe Y, Mizuno T, Suzumura A (2006) Tumor Necrosis Factor-α Induces Neurotoxicity via Glutamate Release from Hemichannels of Activated Microglia in an Autocrine Manner. J Biol Chem 281:21362–21368. https://doi.org/10.1074/jbc.M600504200

    Article  CAS  PubMed  Google Scholar 

  157. Stellwagen D, Beattie EC, Seo JY, Malenka RC (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-α. J Neurosci 25:3219–3228. https://doi.org/10.1523/JNEUROSCI.4486-04.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marinovich M (2003) Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23:8692–8700. https://doi.org/10.1523/jneurosci.23-25-08692.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Roseti C, van Vliet EA, Cifelli P, Ruffolo G, Baayen JC, Di Castro MA, Bertollini C, Limatola C, Aronica E, Vezzani A, Palma E (2015) GABAA currents are decreased by IL-1β in epileptogenic tissue of patients with temporal lobe epilepsy: Implications for ictogenesis. Neurobiol Dis 82:311–320. https://doi.org/10.1016/j.nbd.2015.07.003

    Article  CAS  PubMed  Google Scholar 

  160. Dyomina AV, Zubareva OE, Smolensky IV, Vasilev DS, Zakharova MV, Kovalenko AA, Schwarz AP, Ischenko AM, Zaitsev AV (2020) Anakinra Reduces Epileptogenesis, Provides Neuroprotection, and Attenuates Behavioral Impairments in Rats in the Lithium–Pilocarpine Model of Epilepsy. Pharmaceuticals 13:340. https://doi.org/10.3390/ph13110340

    Article  CAS  PubMed Central  Google Scholar 

  161. Noe FM, Polascheck N, Frigerio F, Bankstahl M, Ravizza T, Marchini S, Beltrame L, Banderó CR, Löscher W, Vezzani A (2013) Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol Dis 59:183–193. https://doi.org/10.1016/j.nbd.2013.07.015

    Article  CAS  PubMed  Google Scholar 

  162. Wan Y, Feng B, You Y, Yu J, Xu C, Dai H, Trapp BD, Shi P, Chen Z, Hu W (2020) Microglial Displacement of GABAergic Synapses Is a Protective Event during Complex Febrile Seizures. Cell Rep 33:108346. https://doi.org/10.1016/j.celrep.2020.108346

    Article  CAS  PubMed  Google Scholar 

  163. Mukherjee S, Arisi GM, Mims K, Hollingsworth G, O’Neil K, Shapiro LA (2020) Neuroinflammatory mechanisms of post-traumatic epilepsy. J Neuroinflam 17:193. https://doi.org/10.1186/s12974-020-01854-w

    Article  Google Scholar 

  164. Boche D, Perry VH, Nicoll JAR (2013) Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39:3–18. https://doi.org/10.1111/nan.12011

    Article  CAS  PubMed  Google Scholar 

  165. Benson MJ, Manzanero S, Borges K (2015) Complex alterations in microglial M1/M2 markers during the development of epilepsy in two mouse models. Epilepsia 56:895–905. https://doi.org/10.1111/epi.12960

    Article  CAS  PubMed  Google Scholar 

  166. Zhao X, Liao Y, Morgan S, Mathur R, Feustel P, Mazurkiewicz J, Qian J, Chang J, Mathern GW, Adamo MA, Ritaccio AL, Gruenthal M, Zhu X, Huang Y (2018) Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy. Cell Rep 22:2080–2093. https://doi.org/10.1016/j.celrep.2018.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zhao X-F, Liao Y, Alam MM, Mathur R, Feustel P, Mazurkiewicz JE, Adamo MA, Zhu XC, Huang Y (2020) Microglial mTOR is Neuronal Protective and Antiepileptogenic in the Pilocarpine Model of Temporal Lobe Epilepsy. J Neurosci 40:7593–7608. https://doi.org/10.1523/JNEUROSCI.2754-19.2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Zhou Q-G, Nemes AD, Lee D, Ro EJ, Zhang J, Nowacki AS, Dymecki SM, Najm IM, Suh H (2018) Chemogenetic silencing of hippocampal neurons suppresses epileptic neural circuits. J Clin Invest 129:310–323. https://doi.org/10.1172/JCI95731

    Article  PubMed  PubMed Central  Google Scholar 

  169. Luo C, Koyama R, Ikegaya Y (2016) Microglia engulf viable newborn cells in the epileptic dentate gyrus. Glia 64:1508–1517. https://doi.org/10.1002/glia.23018

    Article  PubMed  Google Scholar 

  170. Yang F, Liu Z-R, Chen J, Zhang S-J, Quan Q-Y, Huang Y-G, Jiang W (2010) Roles of astrocytes and microglia in seizure-induced aberrant neurogenesis in the hippocampus of adult rats. J Neurosci Res 88:519–529. https://doi.org/10.1002/jnr.22224

    Article  CAS  PubMed  Google Scholar 

  171. Heo K, Cho Y-J, Cho K-J, Kim H-W, Kim H-J, Shin HY, Lee BI, Kim GW (2006) Minocycline inhibits caspase-dependent and -independent cell death pathways and is neuroprotective against hippocampal damage after treatment with kainic acid in mice. Neurosci Lett 398:195–200. https://doi.org/10.1016/j.neulet.2006.01.027

    Article  CAS  PubMed  Google Scholar 

  172. Wang N, Mi X, Gao B, Gu J, Wang W, Zhang Y, Wang X (2015) Minocycline inhibits brain inflammation and attenuates spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neuroscience 287:144–156. https://doi.org/10.1016/j.neuroscience.2014.12.021

    Article  CAS  PubMed  Google Scholar 

  173. Andoh M, Ikegaya Y, Koyama R (2019) Synaptic Pruning by Microglia in Epilepsy. J Clin Med 8:2170. https://doi.org/10.3390/jcm8122170

    Article  CAS  PubMed Central  Google Scholar 

  174. Wyatt-Johnson SK, Brewster AL (2020) Emerging Roles for Microglial Phagocytic Signaling in Epilepsy. Epilepsy Curr 20:33–38. https://doi.org/10.1177/1535759719890336

    Article  PubMed  Google Scholar 

  175. Najjar S, Pearlman D, Miller DC, Devinsky O (2011) Refractory Epilepsy Associated With Microglial Activation. Neurologist 17:249–254. https://doi.org/10.1097/NRL.0b013e31822aad04

    Article  PubMed  Google Scholar 

  176. Aronica E, Gorter JA, Redeker S, Ramkema M, Spliet WGM, van Rijen PC, Leenstra S, Troost D (2005) Distribution, characterization and clinical significance of microglia in glioneuronal tumours from patients with chronic intractable epilepsy. Neuropathol Appl Neurobiol 31:280–291. https://doi.org/10.1111/j.1365-2990.2004.00636.x

    Article  CAS  PubMed  Google Scholar 

  177. Milior G, Morin-Brureau M, Chali F, Le Duigou C, Savary E, Huberfeld G, Rouach N, Pallud J, Capelle L, Navarro V, Mathon B, Clemenceau S, Miles R (2020) Distinct P2Y Receptors Mediate Extension and Retraction of Microglial Processes in Epileptic and Peritumoral Human Tissue. J Neurosci 40:1373–1388. https://doi.org/10.1523/JNEUROSCI.0218-19.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Russian Text © The Author(s), 2021, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2021, Vol. 107, Nos. 4–5, pp. 492–517https://doi.org/10.31857/S0869813921040166.

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Zaitsev, А.V., Amakhin, D.V., Dyomina, A.V. et al. Synaptic Dysfunction in Epilepsy. J Evol Biochem Phys 57, 542–563 (2021). https://doi.org/10.1134/S002209302103008X

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