Glutamate Signaling Pathway in Absence Epilepsy: Possible Role of Ionotropic AMPA Glutamate Receptor Type 1 Subunit

Document Type : Research article


1 Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.

2 Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.

3 Department of Nano biotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.

4 Department of Virology, School of Public Health, International Campus, Tehran University of Medical Sciences, Tehran, Iran.


AMPA receptors, consisting of glutamate receptor type1 (GluR1) subunit are involved in the pathophysiology of some neurological disorders. In this study, the role of the GluR1 subunit in the development, as well as features of absence seizures were assessed. Both Wistar and WAG/Rij (a genetic animal model of absence epilepsy) rats with 2 and 6-month ages were included in the study. The expression of GluR1 was measured in the somatosensory cortex. Moreover, the effects of pharmacological activation and inhibition of AMPA receptors on the characteristic of absence epileptic activities were evaluated by microinjection of agonist or antagonist of AMPA receptors on the somatosensory cortex in the epileptic WAG/Rij rats. Distribution of the GluR1 subunit of AMPA receptors in the both IV (p < 0.001) and VI (p < 0.01) layers of the somatosensory cortex in the epileptic WAG/Rij rats was higher than non-epileptic animals. In addition, the microinjection of AMPA receptors agonist on the somatosensory cortex of the WAG/Rij rats increased both amplitude (p < 0.01) and duration (p < 0.001) of spike-wave discharges (SWDs), while injection of antagonist reduced amplitude (p < 0.001) and duration (p < 0.01) of SWDs in the somatosensory cortex of epileptic rats. The high expression of GluR1 in the somatosensory cortex of epileptic rats suggests the role of AMPA receptors consisting of the GluR1 subunit in the development of absence seizures. The modulatory effects AMPA receptors on the feature of SWDs suggest the potential of AMPA receptors antagonists as a therapeutic target for absence epilepsy.

Graphical Abstract

Glutamate Signaling Pathway in Absence Epilepsy: Possible Role of Ionotropic AMPA Glutamate Receptor Type 1 Subunit


  1. Bilo L, Pappatà S, De Simone R, Meo R. The syndrome of absence status epilepsy: review of the literature. Epilepsy Res treat. 2014;2014.
  2. Bal T, von Krosigk M, McCormick DA. Role of the ferret perigeniculate nucleus in the generation of synchronized oscillations in vitro. J. Physiol. 1995;483(3):665-85.
  3. Avanzini G, Panzica F, De Curtis M. The role of the thalamus in vigilance and epileptogenic mechanisms. Clin. Neurophysiol. 2000;111:S19-S26.
  4. Polack PO, Charpier S. Intracellular activity of cortical and thalamic neurones during high‐voltage rhythmic spike discharge in Long‐Evans rats in vivo. J. Physiol. 2006;571(2):461-76.
  5. Depaulis A, Charpier S. Pathophysiology of absence epilepsy: Insights from genetic models. Neurosci. Lett. 2017.
  6. Seneviratne U, Cook M, D'souza W. Focal abnormalities in idiopathic generalized epilepsy: a critical review of the literature. Epilepsia. 2014;55(8):1157-69.
  7. Polack P-O, Mahon S, Chavez M, Charpier S. Inactivation of the somatosensory cortex prevents paroxysmal oscillations in cortical and related thalamic neurons in a genetic model of absence epilepsy. Cereb. Cortex. 2009;19(9):2078-91.
  8. Russo E, Citraro R, Constanti A, Leo A, Lüttjohann A, van Luijtelaar G, et al. Upholding WAG/Rij rats as a model of absence epileptogenesis: hidden mechanisms and a new theory on seizure development. ‎Neurosci. Biobehav. Rev. 2016;71:388-408.
  9. Coenen A, Van Luijtelaar E. Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats. Behav. Genet. 2003;33(6):635-55.
  10. Hall JE. Guyton and Hall textbook of medical physiology e-Book: Elsevier Health Sciences; 2015.
  11. Karimzadeh F, Mousavi SMM, Ghadiri T, Jafarian M, Soleimani M, Sadeghi SM, et al. The Modulatory Effect of Metabotropic Glutamate Receptor Type-1α on Spike-Wave Discharges in WAG/Rij Rats. Mol neurobiol. 2016:1-9.
  12. Man H-Y, Sekine-Aizawa Y, Huganir RL. Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking through PKA phosphorylation of the Glu receptor 1 subunit. Proc Natl Acad Sci . 2007;104(9):3579-84.
  13. Platt SR. The role of glutamate in central nervous system health and disease–a review. Vet. J. 2007;173(2):278-86.
  14. Greger IH, Ziff EB, Penn AC. Molecular determinants of AMPA receptor subunit assembly. Trends Neurosci. 2007;30(8):407-16.
  15. Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. Nutr. J. 2000;130(4):1007S-15S.
  16. Weiser T. AMPA receptor antagonists for the treatment of stroke. CNS Neurol Disord Drug Targets. 2005;4(2):153-9.
  17. Rogawski MA. AMPA receptors as a molecular target in epilepsy therapy. Acta Neurol. Scand. 2013;127:9-18.
  18. Beneyto M, Meador‐Woodruff JH. Expression of transcripts encoding AMPA receptor subunits and associated postsynaptic proteins in the macaque brain. J. Comp. Neurol. 2004;468(4):530-54.
  19. Karimzadeh F, Mousavi SMM, Alipour F, Ravandi HH, Kovac S, Gorji A. Developmental changes in Notch1 and NLE1 expression in a genetic model of absence epilepsy. Brain Struct Funct. 2017;222(6):2773-85.
  20. Paxinos G, Watson C. The rat brain atlas in stereotaxic coordinates. San Diego: Academic. 1998.
  21. Citraro R, Russo E, Gratteri S, Di Paola ED, Ibbadu GF, Curinga C, et al. Effects of non-competitive AMPA receptor antagonists injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy. Neuropharmacol. 2006;51(6):1058-67.
  22. Ghalandari-Shamami M, Hassanpour-Ezatti M, Haghparast A. Intra-accumbal NMDA but not AMPA/kainate receptor antagonist attenuates WIN55, 212-2 cannabinoid receptor agonist-induced antinociception in the basolateral amygdala in a rat model of acute pain. Pharmacol Biochem Behav. 2011;100(2):213-9.
  23. Fan X, Hughes KE, Jinnah H, Hess EJ. Selective and sustained α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation in cerebellum induces dystonia in mice. J. Pharmacol. Exp. Ther. 2012;340(3):733-41.
  24. Mehrabi S, Sanadgol N, Barati M, Shahbazi A, Vahabzadeh G, Barzroudi M, et al. Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy. Metab Brain Dis.. 2018;33(1):107-14.
  25. Karimzadeh F, Soleimani M, Mehdizadeh M, Jafarian M, Mohamadpour M, Kazemi H, et al. Diminution of the NMDA receptor NR2B subunit in cortical and subcortical areas of WAG/Rij rats. Synapse. 2013;67(12):839-46.
  26. Ridding M, Rothwell J, Inzelberg R. Changes in excitability of motor cortical circuitry in patients with Parkinson's disease. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 1995;37(2):181-8.
  27. Geevasinga N, Menon P, Sue C, Kumar K, Ng K, Yiannikas C, et al. Cortical excitability changes distinguish the motor neuron disease phenotypes from hereditary spastic paraplegia. Eur. J. Neurol. 2015;22(5):826-e58.
  28. Menon P, Geevasinga N, Van Den Bos M, Yiannikas C, Kiernan M, Vucic S. Cortical hyperexcitability and disease spread in amyotrophic lateral sclerosis. Eur. J. Neurol. 2017;24(6):816-24.
  29. Stern WM, Desikan M, Hoad D, Jaffer F, Strigaro G, Sander JW, et al. Spontaneously fluctuating motor cortex excitability in alternating hemiplegia of childhood: a transcranial magnetic stimulation study. PLoS One. 2016;11(3):e0151667.
  30. Khedr EM, Ahmed MA, Ali AM, Badry R, Rothwell JC. Changes in motor cortical excitability in patients with Sydenham's chorea. Mov. Disord. 2015;30(2):259-62.
  31. Pickard L, Noel J, Henley JM, Collingridge GL, Molnar E. Developmental changes in synaptic AMPA and NMDA receptor distribution and AMPA receptor subunit composition in living hippocampal neurons. J. Neurosci. 2000;20(21):7922-31.
  32. Henley JM, Wilkinson KA. Synaptic AMPA receptor composition in development, plasticity and disease. Nat. Rev. Neurosci. 2016;17(6):337.
  33. Babb TL, Mathern GW, Leite JP, Pretorius JK, Yeoman KM, Kuhlman PA. Glutamate AMPA receptors in the fascia dentata of human and kainate rat hippocampal epilepsy. Epilepsy Res. 1996;26(1):193-205.
  34. Hosford DA, Crain BJ, Cao Z, Bonhaus DW, Friedman AH, Okazaki M, et al. Increased AMPA-sensitive quisqualate receptor binding and reduced NMDA receptor binding in epileptic human hippocampus. J. Neurosci. 1991;11(2):428-34.
  35. Sherwin AL. Neuroactive amino acids in focally epileptic human brain: a review. Neurochem. Res. 1999;24(11):1385-95.
  36. Ying Z, Babb TL, Comair YG, Bushey M, Touhalisky K. Increased densities of AMPA GluR1 subunit proteins and presynaptic mossy fiber sprouting in the fascia dentata of human hippocampal epilepsy. Brain Res. 1998;798(1-2):239-46.
  37. Grooms SY, Opitz T, Bennett MV, Zukin RS. Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death. Proc. Natl. Acad. Sci. 2000;97(7):3631-6.
  38. Galic M, Riazi K, Henderson A, Tsutsui S, Pittman Q. Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats. Neurobiol. Dis. 2009;36(2):343-51.
  39. Shehata M, Matsumura H, Okubo-Suzuki R, Ohkawa N, Inokuchi K. Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J. Neurosci. 2012;32(30):10413-22.
  40. Bakker J, Basedow FJ, Dekker AD, Papantoniou C. Phosphorylation of AMPA-type glutamate receptors: the trigger of epileptogenesis? J. Neurosci. 2013;33(14):5879-80.
  41. Steinhäuser C. Role of Astrocyte Dysfunction in Epilepsy q. 2017.
  42. Seifert G, Schröder W, Hinterkeuser S, Schumacher T, Schramm J, Steinhäuser C. Changes in flip/flop splicing of astroglial AMPA receptors in human temporal lobe epilepsy. Epilepsia. 2002;43:162-7.
  43. Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, et al. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J. Neurosci. 2004;24(36):7829-36.
  44. Bredt DS, Nicoll RA. AMPA receptor trafficking at excitatory synapses. Neuron. 2003;40(2):361-79.
  45. Powell KL, Kyi M, Reid CA, Paradiso L, D'Abaco G, Kaye A, et al. Genetic absence epilepsy rats from Strasbourg have increased corticothalamic expression of stargazin. Neurobiol. Dis. 2008;31(2):261-5.
  46. Kennard J, Barmanray R, Sampurno S, Ozturk E, Reid C, Paradiso L, et al. Stargazin and AMPA receptor membrane expression is increased in the somatosensory cortex of Genetic Absence Epilepsy Rats from Strasbourg. Neurobiol. Dis. 2011;42(1):48-54.
  47. Sadleir L, Farrell K, Smith S, Connolly M, Scheffer I. Electroclinical features of absence seizures in childhood absence epilepsy. Neurology. 2006;67(3):413-8.
  48. Polack P-O, Guillemain I, Hu E, Deransart C, Depaulis A, Charpier S. Deep layer somatosensory cortical neurons initiate spike-and-wave discharges in a genetic model of absence seizures. J. Neurosci. 2007;27(24):6590-9.
  49. Moldrich RX, Chapman AG, De Sarro G, Meldrum BS. Glutamate metabotropic receptors as targets for drug therapy in epilepsy. Eur. J. Pharmacol. 2003;476(1-2):3-16.
  50. Çavuş I, Romanyshyn JC, Kennard JT, Farooque P, Williamson A, Eid T, et al. Elevated basal glutamate and unchanged glutamine and GABA in refractory epilepsy: Microdialysis study of 79 patients at the yale epilepsy surgery program. Ann. Neurol. 2016;80(1):35-45.
  51. Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics. 2007;4(1):18-61.
  52. Lee H-K, Takamiya K, He K, Song L, Huganir RL. Specific roles of AMPA receptor subunit GluR1 (GluA1) phosphorylation sites in regulating synaptic plasticity in the CA1 region of hippocampus. J. Neurophysiol. 2009;103(1):479-89.
  53. Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr. 2011;11(2):56-63.
  54. Koh S, Tibayan FD, Simpson JN, Jensen FE. NBQX or topiramate treatment after perinatal hypoxia‐induced seizures prevents later increases in seizure‐induced neuronal injury. Epilepsia. 2004;45(6):569-75.
  55. McBain C, Boden P, Hill R. The kainate/quisqualate receptor antagonist, CNQX, blocks the fast component of spontaneous epileptiform activity in organotypic cultures of rat hippocampus. Neurosci. Lett. 1988;93(2-3):341-5.
  56. Neuman R, Ben-Ari Y, Cherubini E. Antagonism of spontaneous and evoked bursts by 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) in the CA3 region of the in vitro hippocampus. Brain Res. 1988;474(1):201-3.
  57. Lee W-L, Hablitz JJ. Involvement of non-NMDA receptors in picrotoxin-induced epileptiform activity in the hippocampus. Neurosci. Lett. 1989;107(1-3):129-34.
  58. Rakhade SN, Zhou C, Aujla PK, Fishman R, Sucher NJ, Jensen FE. Early alterations of AMPA receptors mediate synaptic potentiation induced by neonatal seizures. J. Neurosci. 2008;28(32):7979-90.