The Journal of Physiological Sciences

, Volume 65, Supplement 2, pp S3–S10 | Cite as

GluN2A/B ratio elevation induced by cortical spreading depression: electrophysiological and quantitative studies of the hippocampus

  • Panupong Hansrivijit
  • Suteera Vibulyaseck
  • Montree Maneepark
  • Anan Srikiatkhachorn
  • Saknan Bongsebandhu-phubhakdiEmail author
Original Paper


Cortical spreading depression (CSD), an underlying mechanism of migraine aura, propagates to the hippocampus, and might explain hippocampusassociated symptoms during migraine attack. We hypothesised that this process is, some parts, mediated by NMDA receptors. By using a rat model, CSD was elicited by solid KCl for 45 minutes prior to electrophysiological and quantitative analyses. The result from electrophysiological study was the ratio of glutamate NMDA receptor 2A and 2B subunits (GluN2A/B). Total NMDA receptor response was isolated using an AMPA antagonist, prior to a GluN2B receptor antagonist. The GluN2A/B ratio was calculated by dividing the remaining NMDA-mediated field-excitatory synaptic potentials (fEPSP) with the subtracted difference of NMDAmediated fEPSP. Western blot analysis of the hippocampus was performed to confirm the quantitative change of GluN2A/B ratio. In hippocampal slice study (n = 12), the GluN2A/B ratio of hippocampal fEPSP was significantly increased in CSD group. Western blot analysis (n = 30) revealed an increase in GluN2A subunits and a decrease in GluN2B subunits in the hippocampus ipsilateral to the CSD induction. Our current study revealed that GluN2A/B ratio was shown to be elevated following CSD stimulation by increasing the total number of GluN2A while reducing the total number of GluN2B subunits. This ratio was demonstrated to be associated with synaptic plasticity of the hippocampus in numerous studies. In conclusion, we showed that CSD increased GluN2A/B ratio, in turn, would result in altered synaptic plasticity. Our findings provide a probable implication on the correlation of migraine aura and hippocampusassociated symptoms.


NMDA receptors  migraine aura  transient global amnesia (TGA)  hippocampal spreading depression  long-term potentiation (LTP)  AMPA receptors 


  1. 1.
    Obrenovitch TP, Zilkha E (1995) High extracellular potassium, and not extracellular glutamate, is required for the propagation of spreading depression. J Neurophysiol 73:2107–2114.CrossRefGoogle Scholar
  2. 2.
    Hadjikhani N, Sanchez del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, Kwong KK, Cutrer FM, Rosen BR, Tootell RB, et al (2001) Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA 98:4687–4692.CrossRefGoogle Scholar
  3. 3.
    Chen WT, Lin YY, Fuh JL, Hamalainen MS, Ko YC, Wang SJ (2011) Sustained visual cortex hyperexcitability in migraine with persistent visual aura. Brain 134:2387–2395.CrossRefGoogle Scholar
  4. 4.
    Leao AAP (1944) Spreading depression of activity in the cerebral cortex. J Neurophysiol 7:359–390.CrossRefGoogle Scholar
  5. 5.
    Crowell GF, Stump DA, Biller J, McHenry LC Jr, Toole JF (1984) The transient global amnesia-migraine connection. Arch Neurol 41(1):75–79.CrossRefGoogle Scholar
  6. 6.
    Lin KH, Chen YT, Fuh JL, Li SY, Chen TJ, Tang CH, Wang SJ (2014) Migraine is associated with a higher risk of transient global amnesia: a nationwide cohort study. Eur J Neurol 21:718–724.CrossRefGoogle Scholar
  7. 7.
    Olesen J, Jorgensen MB (1986) Leao’s spreading depression in the hippocampus explains transient global amnesia. A hypothesis. Acta Neurol Scand 73:219–220.CrossRefGoogle Scholar
  8. 8.
    Eikermann-Haerter K, Yuzawa I, Qin T, Wang Y, Baek K, Kim YR, Hoffmann U, Dilekoz E, Waeber C, Ferrari MD, van den Maagdenberg AMJM, Moskowitz MA, Ayata, C (2011) Enhanced Subcortical Spreading Depression in Familial Hemiplegic Migraine Type 1 Mutant Mice. J Neurosci 31(15): 5755–5763.CrossRefGoogle Scholar
  9. 9.
    Maneepark M, Srikiatkhachorn A, Bongsebandhu-phubhakdi S (2012) Involvement of AMPA receptors in CSD-induced impairment of LTP in the hippocampus. Headache 52:1535–1545.CrossRefGoogle Scholar
  10. 10.
    Laurie DJ, Bartke I, Schoepfer R, Naujoks K, Seeburg PH (1997) Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res Mol Brain Res 51:23–32.CrossRefGoogle Scholar
  11. 11.
    Philpot BD, Cho KK, Bear MF (2007) Obligatory role of NR2A for metaplasticity in visual cortex. Neuron 53:495–502.CrossRefGoogle Scholar
  12. 12.
    Xu Z, Chen RQ, Gu QH, Yan JZ, Wang SH, Liu SY, Lu W (2009) Metaplastic regulation of long-term potentiation/longterm depression threshold by activity-dependent changes of NR2A/NR2B ratio. J Neurosci 29:8764–8773.CrossRefGoogle Scholar
  13. 13.
    Kopp C, Longordo F, Nicholson JR, Luthi A (2011) Insufficient sleep reversibly alters bidirectional synaptic plasticity and NMDA receptor function. J Neurosci 26:12456–12465.CrossRefGoogle Scholar
  14. 14.
    Kudo C, Toyama M, Boku A, Hanamoto H, Morimoto Y, Sugimura M, Niwa H (2013) Anesthetic effects on susceptibility to cortical spreading depression. Neuropharmacology 67:32–36.CrossRefGoogle Scholar
  15. 15.
    Paxinos G, Watson C (2013) The rat brain in stereotaxic coordinates. 7th edition. Elsevier, Academic Press, New York, NY.Google Scholar
  16. 16.
    MacDougall MJ, Howland JG (2013) Acute stress and hippocampal output: exploring dorsal CA1 and subicular synaptic plasticity simultaneously in anesthetized rats. Physiol Rep 1(2):e00035.CrossRefGoogle Scholar
  17. 17.
    Scimemi A, Fine A, Kullmann DM, Rusakov DA (2004) NR2B-containing receptors mediate cross talk among hippocampal synapses. J Neurosci 24:4767–4777.CrossRefGoogle Scholar
  18. 18.
    Wernsmann B, Pape H, Speckmann E, Gorji A (2006) Effect of cortical spreading depression on synaptic transmission of rat hippocampal tissues. Eur J Neurosci 23:1103–1110.CrossRefGoogle Scholar
  19. 19.
    Martens-Mantai T, Speckmann E, Gorji A (2014) Propagation of cortical spreading depression into the hippocampus: the role of the entorhinal cortex. Synapse 68:574–584.CrossRefGoogle Scholar
  20. 20.
    Kunkler PE, Kraig RP (2003) Hippocampal spreading depression bilaterally activates the caudal trigeminal nucleus in rodents. Hippocampus 13:835–844.CrossRefGoogle Scholar
  21. 21.
    De Curtis M, Pare D (2004) The rhinal cortices: A wall of inhibition between the neocortex and the hippocampus. Prog Neu robiol 74:101–110.CrossRefGoogle Scholar
  22. 22.
    Pelletier JG, Apergis J, Pare D (2004) Low probability transmission of neocortical and entorhinal impulses through the perirhinal cortex. J Neurophysiol 91:2079–2089.CrossRefGoogle Scholar
  23. 23.
    Weitlauf C, Honse Y, Auberson YP, Mishina M, Lovinger DM, Winder DG (2005) Activation of NR2A-Containing NMDA Receptors Is Not Obligatory for NMDA Receptor-Dependent Long-Term Potentiation. J Neurosci 25:8386–8390.CrossRefGoogle Scholar
  24. 24.
    Philpot BD, Cho KK, Bear MF (2007) Obligatory role of NR2A for metaplasticity in visual cortex. Neuron 53:495–502.CrossRefGoogle Scholar
  25. 25.
    Cui Z, Feng R, Jacobs S, Duan Y, Wang H, Cao X, Tsien JZ (2013) Increased NR2A:NR2B ratio compresses long-term depression range and constrains long-term memory. Sci Rep 3:1036.CrossRefGoogle Scholar
  26. 26.
    Erreger K, Dravid SM, Banke TG, Wyllie DJA, Traynelis SF (2005) Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signaling profiles. J Physiol 563.2:345–358.CrossRefGoogle Scholar
  27. 27.
    Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ (1999) Genetic enhancement of learning and memory in mice. Nature 401:63–69.CrossRefGoogle Scholar
  28. 28.
    Kiyama Y, Manabe T, Sakimura K, Kawakami F, Mori H, Mishina M (1998) Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor epsilon1 subunit. J Neurosci 18:6704–6712.CrossRefGoogle Scholar
  29. 29.
    Sprengel R, Suchanek B, Amico C, Brusa R, Burnashev N, Rozov A, Hvalby O, Jensen V, Paulsen O, Andersen P, et al. (1998) Importance of the intracellular domain of NR2 subunits for NMDA receptor fu nction in vivo. Cell 92:279–289.CrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan 2015

Authors and Affiliations

  • Panupong Hansrivijit
    • 1
  • Suteera Vibulyaseck
    • 1
    • 2
  • Montree Maneepark
    • 1
    • 3
  • Anan Srikiatkhachorn
    • 1
  • Saknan Bongsebandhu-phubhakdi
    • 1
    Email author
  1. 1.Department of Physiology, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  2. 2.Medical Research InstituteTokyo Medical and Dental UniversityTokyoJapan
  3. 3.Department of Biology, Faculty of ScienceSrinakharinwirot UniversityBangkokThailand

Personalised recommendations