Abstract
1. Molecular mechanisms underlying increased hippocampal excitability in human temporal lobe epilepsy (TLE) are largely unknown. A disturbance of the imbalance between excitatory and inhibitory neurotransmission pathways in the epileptic hippocampus may contribute substantially to a decreased seizure threshold.
2. We have extended the investigation whether TLE is associated with changes in the expression of GAD67 and NMDAR1 by assessing the relative amounts of the mRNAs in human hippocampal samples by means of semiquantitative RT-PCR. The samples included 16 hippocampal slices obtained at surgery from intractable TLE (HS, n = 14; non-HS, n = 2) and 3 postmortem control hippocampi.
3. The ratio for the GAD/NMDAR1 transcripts was significantly higher in TLE cases when compared to the nonepileptic samples. Such findings are mainly a consequence of the increased amounts of GAD mRNA detected in the epileptic hippocampus. Compared with nonepileptic samples, and without correction for neuron losses, the amounts of NMDAR1 mRNA in HS are slightly reduced, and in the non-HS samples they are significantly increased, which is consistent with an increase of NMDAR1 in the hippocampal remaining neurons, as previously reported.
4. Our results also contribute to the indication of GAD67 mRNA upregulation in human TLE. A possible functional implication for the increased GAD mRNA levels could be a mechanism to reduce neuronal hiperexcitability, synchronization, and/or the spread of seizure.
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REFERENCES
Babb, T. L., Brown, W. J., Pretorius, J., Davenport, C., Lieb, J. P., and Crandall, P. H. (1984). Temporal lobe volumetric cell densities in temporal lobe epilepsy. Epilepsia 25:729–740.
Babb, T. L., Pretorius, J. K., Kupfer, W. R., and Crandall, P. H. (1989). Glutamate descarboxylaseimmunoreactive neurons are preserved in human epileptic hippocampus. J. Neurosci. 9:2562–2574.
Bayer, T. A., Wiestler, O. D., and Wolf, H. K. (1995). Hippocampal loss of N-methyl-D-aspartate receptor subunit 1 mRNA in chronic temporal lobe epilepsy. Acta Neuropathol. (Berl.) 89:446–450.
Blümck, I., Becker, A. J., Klein, C., Scheiwe, C., Lie, A. A., Beck, H., Waha, A., Friedl, M. G., Kuhn, R., Emson, P., Elger, C., and Wiestler, O. D. (2000). Temporal lobe epilepsy associated up-regulation of metabotropic glutamate receptors: Correlated changes in mGluR1 mRNA and protein expression in experimental animals and human patients. J. Neuropathol. Exp. Neurol. 59:1–10.
Blümcke, I., Beck, H., Lie, A. A., and Wiestler, O. D. (1999). Molecular neuropathology of human mesial temporal lobe epilepsy. Epilepsy Res. 36:205–223.
Cavalheiro, E. A. (1990). GAD-immunoreactive neurons are preserved in the hippocampus of rats with spontaneous recurrent seizures. Braz. J. Med. Biol. Res. 23:555–558.
Coyle, J. T., and Puttfarcken, P. (1993). Oxidative stress, glutamate, and degenerative disorders. Science 262:689–695.
Delfs, J. M., Ciaramitaro, V. M., Soghomonian, J.-J., and Chesselet, M.-F. (1996). Unilateral nigrostriatal lesions induce a bilateral increase in glutamate decarboxylase messenger RNA in the reticular thalamic nucleus. Neuroscience 71:383–395.
Esclapez, M., Hirsch, J. C., Khazipov, R., Ben-Ari, Y., and Bernard, C. (1997). Operative GABAergic inhibition in hippocampal CA1 pyramidal neurons in experimental epilepsy. Proc. Natl. Acad. Sci. U.S.A. 28:12151–12156.
Esclapez, M., and Houser, C. R. (1999). Up-regulation of GAD65 and GAD67 in remaining hippocampal GABA neurons in a model of temporal lobe epilepsy. J. Comp. Neurol. 412:488–505.
García-Ladona, F. J., Palacios, J. M., Probst, A., Wieser, H. G., and Mengod, G. (1994). Excitatory amino acid AMPA receptor mRNA localization in several regions of normal and neurological disease affected brain. An in situ hybridization study. Brain Res. Mol. Brain Res. 21:75–84.
Hollmann, M., and Heinemann, S. (1994). Cloned glutamate receptors. Annu. Rev. Neurosci. 17:31–108.
Kraus, J. E., Yeh, G. C., Bonhaus, D. W., Nadler, J. V., 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.
Lee, S., Miskovisky, J., Williamson, J., Howels, R., Devinsky, O., Lothman, E., and Christakos, S. (1994). Changes in glutamate receptor and proenkephalin gene expression after kindled seizures. Brain Res. Mol. Brain Res. 24:34–42.
Leite, J. P., Terra-Bustamante, V. C., Fernandes, R. M., Santos, A. C., Chimelli, L., Sakamoto, A. C., Assirati, J. A., and Takayanagui, O. M. (2000). Calcified neurocysticercotic lesions and postsurgery seizure control in temporal lobe epilepsy. Neurology 28:1485–1491.
Lorente de Nó, R. (1934). Studies on the structure of the cerebral córtex. II. Continuation of the study of the ammonic system. J. Psychol. Neurol. 46:113–177.
Mathern, G. H., Babb, T. L., Leite, J. P., Pretorius, J. K., Yeoman, K. M., and Kuhlman, P. A. (1996). The pathogenic and progressive features of chronic human hippocampal epilepsy. Epilepsy Res. 26:151–161.
Mathern, G. H., Babb, T. L., Pretorius, J. K., and Leite, J. P. (1995). Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human fascia dentate. J. Neurosci. 15:3990–4004.
Mathern, G. H., Pretorius, J. K., Kornblum, H. I., Mendoza, D., Lozada, A., Leite, J. P., Chimelli, L. M. C., Fried, I., Sakamoto, A. C., Assirati, J. A., Lévesque, M. F., Adelson, P. D., and Peacock, W. J. (1997). Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients. Brain 120:1937–1959.
Mathern, G. H., Pretorius, J. K., Leite, J. P., Kornblum, H. I., Mendoza, D., Lozada, A., and Bertram, H. I. (1998). Hippocampal AMPA and NMDA mRNA levels and subunit immunoreactivity in human temporal lobe epilepsy patients and a rodent model of chronic mesial limbic epilepsy. Epilepsy Brain Res. 32:154–171.
Mcdonald, J. W., Garafalo, E. A., Hood, T., Sackellares, J. C., Gilman, S., Mckeever, P. E., Troncoso, J. C., and Johnston, M. V. (1991). Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy. Ann. Neurol. 29:529–541.
Mcnamara, J. O. (1999). Emerging insights into the genesis of epilepsy. Nature 399(Suppl.):A15–A22.
Musshoff, U., Schüncke, U., Köhling, R., and Speckmann, E. J. (2000). Alternative splicing of the NMDAR1 glutamate receptor subunit in human temporal lobe epilepsy. Mol. Brain Res. 76:377–384.
Ramírez, M., and Gutiérrez, R. (2001). Activity-dependent expression of GAD67 in the granule cells of the rat hippocampus. Brain Res. 917:139–146.
Soghomonian, J.-J., and Chesselet, M.-F. (1992). Effects of nigrostriatal lesions on the levels of messenger RNAs encoding two isoforms of glutamate decarboxylase in the globus pallidus and entopeduncular nucleus of the rat. Synapse 11:124–133.
Soghomonian, J.-J., Gonzales, C., and Chesselet, M.-F. (1992). Messenger RNAs encoding glutamate decarboxylase are differentially affected by nigrostriatal lesions in subpopulations of striatal neurons. Brain Res. 576:68–79.
Sommer, B., and Seeburg, P. H. (1994). Glutamate receptor channels: Novel properties and new clones. Trends Pharmacol. Sci. 13:291–296.
Ure, J. A., and Perassolo, M. (2000). Update on the pathophysiology of the epilepsies. J. Neurol. Sci. 177:1–17.
Wahlestedt, C., Golanov, E., Yamamoto, S., Yee, F., Ericson, H., Yoo, H., Inturrisi, C. E., and Reis, D. J. (1993). Antisense oligodeoxynucleotydes to NMDA-R1 receptor channel protect cortical neurons from excitoxicity and reduce focal ischaemic infarctions. Nature 363:260–263.
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Neder, L., Valente, V., Carlotti, C.G. et al. Glutamate NMDA Receptor Subunit R1 and GAD mRNA Expression in Human Temporal Lobe Epilepsy. Cell Mol Neurobiol 22, 689–698 (2002). https://doi.org/10.1023/A:1021852907068
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DOI: https://doi.org/10.1023/A:1021852907068