Abstract
“Kindling” is a phenomenon of epileptogenesis, which has been widely used as an experimental model of temporal lobe epilepsy. At the present work we investigated the contribution of NMDA receptors in the Pentylenetetrazol-induced “kindling” model in the mouse brain, by using quantitative autoradiography and the radioactive ligands [3H]MK801 and [3H]L-glutamate (NMDA-sensitive component). One week after establishment of kindling, a small but significant increase in [3H]MK801 as well as NMDA-sensitive [3H]glutamate binding was seen, being restricted to the molecular layer (ML) of the dentate gyrus (DG) and the CA3 region of the hippocampus. These binding augmentations persisted one month after establishment of kindling. A significant increase of NMDA receptor binding was also observed in the cortex-somatosensory and temporal one week after acquisition of the kindled state. The upregulation of NMDA receptors seen in DG and CA3 region of the hippocampus could be associated with the kindling process of this model especially with its maintenance phase, since it persists at long term, is area-specific and consistent with electrophysiological data. The increase of NMDA receptors seen in the cortex of the kindled animals could underlie the hyperexcitability detected by electrophysiological studies in this area.
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REFERENCES
Goddard, G. V., McIntyre, D. C., and Leech, C. K. 1969. A permanent change in brain function resulting from daily electrical stimulation. Exp. Neurol. 25:295–330.
Karler, R., Murphy, V., Calder, L. D., and Turkanis, S. A. 1989. Pentylenetetrazol kindling in mice. Neuropharmacology 28:775–780.
McNamara, J. O., Bonhaus, D. W., Shin, C., Crain, B. J., Gellman, R. L., and Giacchino, J. L. 1985. The kindling model of epilepsy: a critical review. CRC Crit. Rev. in Clin. Neurobiol. 1:341–391.
Kamphuis, W., and Lopes da Silva, F. H. 1990. The kindling model of epilepsy: the role of GAB Aergic inhibition. Neurosci. Res. Com. 6:1–10.
McNamara, J. O., Bonhaus, D. W., Crain, B. J., Gellman, R. L., and Shin, C. 1989. Biochemical and pharmacological studies of neurotransmitters in the kindling model. Pages: 115–160 in Jobe, P. C. and Laird, H. E. II (eds). Neurotransmitters and Epilepsy. Humana Press, Clifton NJ.
Faingold, C. L., and Meldrum, B. S. 1990. Excitatory Amino Acids in Epilepsy. Pages 102–116, in Avoli, M., Gloor, P., Kostopoulos, G., Naquet, R., (eds). Generalized Epilepsy: Neurobiological approaches. Birkhauser, Boston.
Meldrum, B. S. 1994. The role of glutamate in epilepsy and other CNS disorders. Neurology 44(11 Suppl. 8):S14–S23.
Dingledine, R., McBain, C. J., and McNamara, J. O. 1990. Excitatory aminoacids in epilepsy. Trends Pharmacol. Sci. 11:334–338.
Kohr, G., De Koninck, Y., and Mody, I. 1993. Properties of NMDA receptor channels in neurons acutely isolated from epileptic (kindled) rats. J. Neurosci. 13:3612–3627.
Kraus, J. E., Yeh, G. C., Bonhaus, D. W., Nadler, V. J., and McNamara, J. O. 1994. Kindling induces the long-lasting expression of a novel population of NMDA receptors in hippocampal region CA3. J. Neurosci. 14:4196–4205.
Nadler, J. V., Thomson, M. A., and McNamara, J. O. 1994. Kindling reduces sensitivity of CA3 hippocampal pyramidal cells to competitive NMDA receptor antagonists. Neuropharmacology 33:147–153.
Kamphuis, W., Hendriksen, H., Diegenbach, P. C., and Lopes da Silva, F. H. 1995. N-methyl-D-aspartate and kainate receptor gene expression in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis. Neuroscience 67:551–559.
Vezzani, A., Speciale, C., Della Vedova, F., Tamburin, M., and Benatti, L. 1995. Alternative splicing at the C-terminal but not at the N-terminal domain of the NMDA receptor NR1 is altered in the kindled hippocampus. Europ. J. Neurosci. 7:2513–2517.
Barkai, E., Grossman, Y., and Gutnick, M. J. 1994. Long-term changes in neocortical activity after chemical kindling with systemic pentylenetetrazol: an in vitro study. J. Neurophysiol. 72:72–83.
Laurie, D. J., and Seeburg, P. H. 1994. Ligand affinities at recombinant N-methyl-D-aspartate receptors depend on subunit composition. Europ. J. Pharmacol. 268:335–345.
Becker, A., Grecksch, G., Ruthrich, H., Pohle, W., Marx, B., and Mathies, H. 1991. Kindling and its consequences on learning in rats. Behav. Neur. Biol. 57:37–43.
Subramanian, S., and McGonigle, P. 1991. Quantitative autoradiographic characterization of the binding of (+)-5-Methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine([3H]MK-801) in rat brain: regional effects of polyamines. J. Pharmacol. Exp. Ther. 256:811–819.
Monaghan, D. T., and Beaton, J. A. 1991. Quolinate differentiates between forebrain and cerebellar NMDA receptors. Europ. J. Pharmacol. 194:123–125.
Paxinos, G., and Watson, C. 1986. The rat brain in stereotaxic coordinates. 2nd edition, Academic Press, Orlando, Florida.
Golarai, G., Cavazos, J. E., and Sutula, T. P. 1992. Activation of the dentate gyrus by pentylenetetrazol-evoked seizures induces mossy fiber synaptic reorganization. Brain Res. 593:257–264.
Repressa, A., and Ben-Ari, Y. 1992. Kindling is associated with the formation of novel mossy fibre synapses in the CA3 region. Exp. Brain Res. 92:69–78.
Piredda, S., Yonekawa, W., Whittigham, T. S., and Kupferberg, H. J. 1986. Enhanced bursting activity in the CA3 region of the mouse hippocampal slice without long-term potentiation in the dentate gyrus after systemic pentylenetetrazole kindling. Exp. Neurol. 94:659–669.
Ruethrich, H., Grecksch, G., Becker, A., and Krug, M. 1996. Potentiation effects in the dentate gyrus of pentylenetetrazol-kindled rats. Physiol. Behav. 60:455–462.
Schroder, H., Schlichthaar, R., and Krug, M. 1994. Specific [3H]L-Glutamate binding and [3H]D-aspartate release in the hippocampus of rat after pentylenetetrazol kindling and long-term potentiation. Neuroscience 60:337–342.
Angelatou, F., Pagonopoulou, O., and Kostopoulos, G. 1990. Alterations of A1 adenosine receptors in different mouse brain areas after pentylentetrazol induced seizures but not in the epileptic mutant mouse tottering. Brain Res. 534:251–256.
Pagonopoulou, O., Angelatou, F., and Kostopoulos, G. 1993. Effect of Pentylentetrazol-induced seizures on A1 Adenosine receptor regional density in the mouse brain: A quantitative autoradiographic study. Neuroscience 56:711–716.
Angelatou, F., Pagonopoulou, O., and Kostopoulos, G. 1991. Changes in seizure latency corellate with alterations in A1 adenosine receptor binding during daily repeated pentylentetrazolinduced convulsions in different mouse brain areas. Neurosci. Lett. 132:203–206.
Sejima, H., Ito, M., Kishi, K., Tsuda, H., and Shiraishi, H. 1997. Regional excitatory and inhibitory amino acid concentrations in pentylenetetrazol kindling and kindled rat brain. Brain Dev. 19:171–175.
Sibley, D. R., and Lefkowitz, J. 1985. Molecular mechanisms of receptor desensitization using the b-adrenergic receptor-coupled adenylate cyclase system as a model. Nature 317:124–129.
Porter, N. M., Radulovacki, M., and Green, R. D. 1988. Desensitization of adenosine and dopamine receptors in rat brain after treatment with adenosine analogs. J. Pharmacol. Exp. Ther. 244:218–225.
Fantollahi, Y., Motamedi, F., Semnanian, S., and Zardoshti, M. 1997. Examination of persistent effects of repeated administration of pentylenetetrazol on rat hippocampal CA1: evidence from in vitro study on hippocampal slices. Brain Res. 758:92–98.
Krug, M., Koch, M., Grecksch, G., and Schulzeck, K. 1997. Pentyleneterazol-kindling changes the ability to induce potentiation phenomena in the hippocampal CA1 region. Physiol. Behav. 62:721–727.
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Ekonomou, A., Angelatou, F. Upregulation of NMDA Receptors in Hippocampus and Cortex in the Pentylenetetrazol-Induced “Kindling” Model of Epilepsy. Neurochem Res 24, 1515–1522 (1999). https://doi.org/10.1023/A:1021143813935
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DOI: https://doi.org/10.1023/A:1021143813935