Abstract
Synaptotagmin I is a key synaptic protein involved in both exocytosis and endocytosis. We aimed to investigate Synaptotagmin I expression in the anterior temporal neocortex of epilepsy patients, and to explore the possible role of Synaptotagmin I in refractory epilepsy. In the present study, 30 epilepsy patients were divided into refractory epilepsy and non-refractory epilepsy groups, another 15 histologically normal anterior temporal lobes from head trauma patients were used as control group. The results were compared among different groups. The findings were consistently observed using immunohistochemistry, immunofluorescence, and Western blotting technique. Synaptotagmin I was mainly expressed in the cytoplasm and cytomembrane of neurons. The expression of Synaptotagmin I in refractory epilepsy group was significantly higher than that in the control and non-refractory epilepsy groups. These findings provide new information in the epileptogenesis of refractory epilepsy, and suggest that Synaptotagmin I might be involved in human refractory epilepsy. Further studies will be required to elucidate the mechanism by which Synaptotagmin I plays role in refractory epilepsy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adolfsen, B., & Littleton, J. T. (2001). Genetic and molecular analysis of the synaptotagmin family. Cellular and Molecular Life Sciences, 58, 393–402. doi:10.1007/PL00000865.
Bai, J., Wang, P., & Chapman, E. R. (2002). C2A activates a cryptic Ca2+-triggered membrane penetration activity within the C2B domain of synaptotagmin I. Proceedings of the National Academy of Sciences of the United States of America, 99, 1665–1670. doi:10.1073/pnas.032541099.
Bai, J., Wang, C. T., Richards, D. A., Jackson, M. B., & Chapman, E. R. (2004). Fusion pore dynamics are regulated by synaptotagmin*t-SNARE interactions. Neuron, 41, 929–942. doi:10.1016/S0896-6273(04)00117-5.
Bhalla, A., Chicka, M. C., Tucker, W. C., & Chapman, E. R. (2006). Ca(2+)-synaptotagmin directly regulates t-SNARE function during reconstituted membrane fusion. Nature Structural & Molecular Biology, 13, 323–330. doi:10.1038/nsmb1076.
Dai, H., Shen, N., Araç, D., & Rizo, J. (2007). A quaternary SNARE-synaptotagmin-Ca2+-phospholipid complex in neurotransmitter release. Journal of Molecular Biology, 367, 848–863. doi:10.1016/j.jmb.2007.01.040.
During, M. J., & Spencer, D. D. (1993). Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet, 341, 1607–1610. doi:10.1016/0140-6736(93)90754-5.
Fernández-Chacón, R., Königstorfer, A., Gerber, S. H., et al. (2001). Synaptotagmin I functions as a calcium regulator of release probability. Nature, 410, 41–49. doi:10.1038/35065004.
French, J. A. (2007). Refractory epilepsy: clinical overview. Epilepsia, 48(S1), 3–7. doi:10.1111/j.1528-1167.2007.00992.x.
Fukuda, M., & Mikoshiba, K. (2000). Expression of synaptotagmin I or II promotes neurite outgrowth in PC12 cells. Neuroscience Letters, 295, 33–36. doi:10.1016/S0304-3940(00)01585-8.
Haucke, V., & De Camilli, P. (1999). AP-2 recruitment to synaptotagmin stimulated by tyrosine-based endocytic motifs. Science, 285, 1268–1271. doi:10.1126/science.285.5431.1268.
Haucke, V., Wenk, M. R., Chapman, E. R., Farsad, K., & De Camilli, P. (2000). Dual interaction of synaptotagmin with mu2- and alpha-adaptin facilitates clathrin-coated pit nucleation. The EMBO Journal, 19, 6011–6019. doi:10.1093/emboj/19.22.6011.
Jarousse, N., Wilson, J. D., Arac, D., Rizo, J., & Kelly, R. B. (2003). Endocytosis of synaptotagmin 1 is mediated by a novel, tryptophan-containing motif. Traffic (Copenhagen, Denmark), 4, 468–478. doi:10.1034/j.1600-0854.2003.00101.x.
Jorgensen, E. M., Hartwieg, E., Schuske, K., Nonet, M. L., Jin, Y., & Horvitz, H. R. (1995). Defective recycling of synaptic vesicles in synaptotagmin mutants of Caenorhabditis elegans. Nature, 378, 196–199. doi:10.1038/378196a0.
Kabayama, H., Takei, K., Fukuda, M., Ibata, K., & Mikoshiba, K. (1999). Functional involvement of synaptotagmin I/II C2A domain in neurite outgrowth of chick dorsal root ganglion neuron. Neuroscience, 88, 999–1003. doi:10.1016/S0306-4522(98)00547-8.
Kobayashi, S., Ohno, K., Iwakuma, M., Kaneda, Y., & Saji, M. (2002). Synaptotagmin I hypothalamic knockdown prevents amygdaloid seizure-induced damage of hippocampal neurons but not of entorhinal neurons. Neuroscience Research, 44, 455–465. doi:10.1016/S0168-0102(02)00172-4.
Mackler, J. M., Drummond, J. A., Loewen, C. A., Robinson, I. M., & Reist, N. E. (2002). The C(2)B Ca(2+)-binding motif of synaptotagmin is required for synaptic transmission in vivo. Nature, 418, 340–344. doi:10.1038/nature00846.
Martens, S., Kozlov, M. M., & McMahon, H. T. (2007). How synaptotagmin promotes membrane fusion. Science, 316, 1205–1208. doi:10.1126/science.1142614.
Matthew, W. D., Tsavaler, L., & Reichardt, L. F. (1981). Identification of a synaptic vesicle-specific membrane protein with a wide distribution in neuronal and neurosecretory tissue. The Journal of Cell Biology, 91, 257–269. doi:10.1083/jcb.91.1.257.
Meldrum, B. S. (1994). The role of glutamate in epilepsy and other CNS disorders. Neurology, 44(S8), S14–S23.
Meldrum, B. S., Akbar, M. T., & Chapman, A. G. (1999). Glutamate receptors and transporters in genetic and acquired models of epilepsy. Epilepsy Research, 36, 189–204. doi:10.1016/S0920-1211(99)00051-0.
Mikoshiba, K., Fukuda, M., Ibata, K., Kabayama, H., & Mizutani, A. (1999). Role of synaptotagmin, a Ca2+ and inositol polyphosphate binding protein, in neurotransmitter release and neurite outgrowth. Chemistry and Physics of Lipids, 98, 59–67. doi:10.1016/S0009-3084(99)00018-3.
Mizrahi, E. M., Kellaway, P., Grossman, R. G., et al. (1990). Anterior temporal lobectomy and medically refractory temporal lobe epilepsy of childhood. Epilepsia, 31, 302–312. doi:10.1111/j.1528-1157.1990.tb05380.x.
Nicholson-Tomishima, K., & Ryan, T. A. (2004). Kinetic efficiency of endocytosis at mammalian CNS synapses requires synaptotagmin I. Proceedings of the National Academy of Sciences of the United States of America, 101, 16648–16652. doi:10.1073/pnas.0406968101.
Nishiki, T., & Augustine, G. J. (2004). Synaptotagmin I synchronizes transmitter release in mouse hippocampal neurons. The Journal of Neuroscience, 24, 6127–6132. doi:10.1523/JNEUROSCI.1563-04.2004.
Pang, Z. P., Shin, O. H., Meyer, A. C., Rosenmund, C., & Sudhof, T. C. (2006). A gain-of-function mutation in synaptotagmin-1 reveals a critical role of Ca2+-dependent soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex binding in synaptic exocytosis. The Journal of Neuroscience, 26, 12556–12565. doi:10.1523/JNEUROSCI.3804-06.2006.
Proper, E. A., Hoogland, G., Kappen, S. M., et al. (2002). Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain, 125, 32–43. doi:10.1093/brain/awf001.
Rettig, J., & Neher, E. (2002). Emerging roles of presynaptic proteins in Ca2+-triggered exocytosis. Science, 298, 781–785. doi:10.1126/science.1075375.
Robinson, I. M., Ranjan, R., & Schwarz, T. L. (2002). Synaptotagmins I and IV promote transmitter release independently of Ca(2+) binding in the C(2)A domain. Nature, 418, 336–340. doi:10.1038/nature00915.
Stevens, C. F., & Sullivan, J. M. (2003). The synaptotagmin C2A domain is part of the calcium sensor controlling fast synaptic transmission. Neuron, 39, 299–308. doi:10.1016/S0896-6273(03)00432-X.
Südhof, T. C., & Rizo, J. (1996). Synaptotagmins: C2-domain proteins that regulate membrane traffic. Neuron, 17, 379–388. doi:10.1016/S0896-6273(00)80171-3.
Sutula, T., Cascino, G., Cavazos, J., Parada, I., & Ramirez, L. (1989). Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Annals of Neurology, 26, 321–330. doi:10.1002/ana.410260303.
Tocco, G., Bi, X., Vician, L., Lim, I. K., Herschman, H., & Baudry, M. (1996). Two synaptotagmin genes, Syt1 and Syt4, are differentially regulated in adult brain and during postnatal development following kainic acid-induced seizures. Brain Research Molecular Brain Research, 40, 229–239. doi:10.1016/0169-328X(96)00055-1.
Yoshihara, M., & Littleton, J. T. (2002). Synaptotagmin I functions as a calcium sensor to synchronize neurotransmitter release. Neuron, 36, 897–908. doi:10.1016/S0896-6273(02)01065-6.
Zhang, X., Cui, S. S., Wallace, A. E., et al. (2002). Relations between brain pathology and temporal lobe epilepsy. The Journal of Neuroscience, 22, 6052–6061.
Acknowledgments
This material was based on work supported in part by the National Institutes of Health Grants 98-1-3457. We thank the patients and their families for their participation in this study. The authors sincerely thank Tiantan Hospital and Xuanwu Hospital of the Capital University of Medical Sciences, Xinqiao Hospital of the Third Military Medical University for the support in brain tissue procurement, and the local ethics committee and the National Board of the Medical Affairs for their support.
Author information
Authors and Affiliations
Corresponding author
Additional information
Zheng Xiao and Yun Gong contributed equally to this work.
Rights and permissions
About this article
Cite this article
Xiao, Z., Gong, Y., Wang, XF. et al. Altered Expression of Synaptotagmin I In Temporal Lobe Tissue of Patients With Refractory Epilepsy. J Mol Neurosci 38, 193–200 (2009). https://doi.org/10.1007/s12031-008-9143-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-008-9143-x