Skip to main content

Advertisement

Log in

Expression of gLTP in Sympathetic Ganglia of Obese Zucker Rats In Vivo: Molecular Evidence

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Long-term potentiation in sympathetic ganglia (gLTP) is similar to LTP of the hippocampal area CA1 in that its expression involves similar changes in signaling molecules. We have shown previously that the stress-prone, hypertensive obese Zucker rats (OZR) expressed gLTP in sympathetic ganglia and that high blood pressure was reduced by treatment with 5-HT3 receptor antagonists. In the present study, we present additional electrophysiological evidence for the pre-expression of gLTP in sympathetic ganglia from OZR indicated by failure of repetitive stimulation to express gLTP in isolated superior cervical ganglia (SCG) and inhibition of baseline ganglionic transmission by a 5-HT3 receptor antagonist. We have also investigated the role of key signaling molecules in the expression of gLTP in the hypertensive OZR. Immunoblot analysis showed a significant increase in the levels of phosphorylated (P-)CaMKII and protein kinase C gamma (PKCγ) in SCG from OZR. The ratio of P-CaMKII to the total CaMKII was markedly increased in OZR ganglia, suggesting increased phosphorylation of this molecule. Additionally, there was a significant decrease in the levels of calcineurin in ganglia. Furthermore, the neural nitric oxide synthase and hemeoxygenase II, which are essential for the expression of gLTP, were significantly elevated in OZR ganglia. The present findings confirm that ganglia from OZR have expressed gLTP and that synaptic plasticity in sympathetic ganglia may involve a molecular cascade similar to that of LTP of the brain hippocampal area CA1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Alkadhi, K. A., & Altememi, G. F. (1997). Nitric oxide mediates long-term potentiation in rat superior cervical ganglion. Brain Research, 753, 315–317. doi:10.1016/S0006-8993(97)00028-0.

    Article  PubMed  CAS  Google Scholar 

  • Alkadhi, K. A., Alzoubi, K. H., & Aleisa, A. M. (2005a). Plasticity of synaptic transmission in autonomic ganglia. Progress in Neurobiology, 75, 83–108. doi:10.1016/j.pneurobio.2005.02.002.

    Article  PubMed  CAS  Google Scholar 

  • Alkadhi, K. A., Alzoubi, K. H., Aleisa, A. M., Tanner, F. L., & Nimer, A. S. (2005b). Psychosocial stress-induced hypertension results from in vivo expression of long-term potentiation in rat sympathetic ganglia. Neurobiology of Disease, 20, 849–857. doi:10.1016/j.nbd.2005.05.020.

    Article  PubMed  CAS  Google Scholar 

  • Alkadhi, K. A., Al-Hijailan, R. S., Malik, K., & Hogan, Y. H. (2001a). Retrograde carbon monoxide is required for induction of long-term potentiation in rat superior cervical ganglion. The Journal of Neuroscience, 21, 3515–3520.

    PubMed  CAS  Google Scholar 

  • Alkadhi, K. A., Otoom, S. A., Tanner, F. L., Sockwell, D., & Hogan, Y. H. (2001b). Inhibition of ganglionic long-term potentiation decreases blood pressure in spontaneously hypertensive rats. Experimental Biology and Medicine (Maywood, N.J.), 226, 1024–1030.

    CAS  Google Scholar 

  • Alkadhi, K. A., Salgado-Commissariat, D., Hogan, Y. H., & Akpaudo, S. B. (1996). Induction and maintenance of ganglionic long-term potentiation require activation of 5-hydroxytryptamine (5-HT3) receptors. The Journal of Physiology, 496(Pt 2), 479–489.

    PubMed  CAS  Google Scholar 

  • Alonso-deFlorida, F., Morales, M. A., & Minzoni, A. A. (1991). Modulated long-term potentiation in the cat superior cervical ganglion in vivo. Brain Research, 544, 203–210. doi:10.1016/0006-8993(91)90055-Z.

    Article  PubMed  CAS  Google Scholar 

  • Alonso-Galicia, M., Brands, M. W., Zappe, D. H., & Hall, J. E. (1996). Hypertension in obese Zucker rats. Role of angiotensin II and adrenergic activity. Hypertension, 28, 1047–1054.

    PubMed  CAS  Google Scholar 

  • Altememi, G. F., & Alkadhi, K. A. (1999). Nitric oxide is required for the maintenance but not initiation of ganglionic long-term potentiation. Neuroscience, 94, 897–902. doi:10.1016/S0306-4522(99)00362-0.

    Article  PubMed  CAS  Google Scholar 

  • Alzoubi, K. H., Aleisa, A. M., & Alkadhi, K. A. (2008). Expression of gLTP in sympathetic ganglia from stree-hypertensive rats: Molecular evidence. Journal of Molecular Neuroscience, 35, 201–209

    Article  PubMed  CAS  Google Scholar 

  • Alzoubi, K. H., Bedawi, A. S., Aleisa, A. M., & Alkadhi, K. A. (2004). Hypothyroidism impairs long-term potentiation in sympathetic ganglia: Electrophysiologic and molecular studies. Journal of Neuroscience Research, 78, 393–402. doi:10.1002/jnr.20268.

    Article  PubMed  CAS  Google Scholar 

  • Arase, K., Shargill, N. S., & Bray, G. A. (1989). Effects of corticotropin releasing factor on genetically obese (fatty) rats. Physiology & Behavior, 45, 565–570. doi:10.1016/0031-9384(89)90074-7.

    Article  CAS  Google Scholar 

  • Bachoo, M., Heppner, T., Fiekers, J., & Polosa, C. (1992). A role for protein kinase C in long term potentiation of nicotinic transmission in the superior cervical ganglion of the rat. Brain Research, 585, 299–302. doi:10.1016/0006-8993(92)91223-2.

    Article  PubMed  CAS  Google Scholar 

  • Bachoo, M., & Polosa, C. (1992). Preganglionic axons from the third thoracic spinal segment fail to induce long-term potentiation in the superior cervical ganglion of the cat. Canadian Journal of Physiology and Pharmacology, 70(Suppl), S27–S31.

    PubMed  Google Scholar 

  • Boone, J. L. (1991). Stress and hypertension. Primary Care, 18, 623–649.

    PubMed  CAS  Google Scholar 

  • Briggs, C. A., Brown, T. H., & McAfee, D. A. (1985). Neurophysiology and pharmacology of long-term potentiation in the rat sympathetic ganglion. The Journal of Physiology, 359, 503–521.

    PubMed  CAS  Google Scholar 

  • Briggs, C. A., & McAfee, D. A. (1988). Long-term potentiation at nicotinic synapses in the rat superior cervical ganglion. The Journal of Physiology, 404, 129–144.

    PubMed  CAS  Google Scholar 

  • Briggs, C. A., McAfee, D. A., & McCaman, R. E. (1988). Long-term regulation of synaptic acetylcholine release and nicotinic transmission: the role of cyclic AMP. British Journal of Pharmacology, 93, 399–411.

    PubMed  CAS  Google Scholar 

  • Brown, T. H., & McAfee, D. A. (1982). Long-term synaptic potentiation in the superior cervical ganglion. Science, 215, 1411–1413. doi:10.1126/science.6278593.

    Article  PubMed  CAS  Google Scholar 

  • Carlson, S. H., Shelton, J., White, C. R., & Wyss, J. M. (2000). Elevated sympathetic activity contributes to hypertension and salt sensitivity in diabetic obese Zucker rats. Hypertension, 35, 403–408.

    PubMed  CAS  Google Scholar 

  • Cetiner, M., & Bennett, M. R. (1993). Nitric oxide modulation of calcium-activated potassium channels in postganglionic neurones of avian cultured ciliary ganglia. British Journal of Pharmacology, 110, 995–1002.

    PubMed  CAS  Google Scholar 

  • Clapham, J. C., & Turner, N. C. (1997). Effects of the glucocorticoid II receptor antagonist mifepristone on hypertension in the obese Zucker rat. The Journal of Pharmacology and Experimental Therapeutics, 282, 1503–1508.

    PubMed  CAS  Google Scholar 

  • Cunningham, J. J., Calles-Escandon, J., Garrido, F., Carr, D. B., & Bode, H. H. (1986). Hypercorticosteronuria and diminished pituitary responsiveness to corticotropin-releasing factor in obese Zucker rats. Endocrinology, 118, 98–101.

    Article  PubMed  CAS  Google Scholar 

  • Dore, S., Takahashi, M., Ferris, C. D., Zakhary, R., Hester, L. D., Guastella, D., et al. (1999). Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proceedings of the National Academy of Sciences of the United States of America, 96, 2445–2450. doi:10.1073/pnas.96.5.2445.

    Article  PubMed  CAS  Google Scholar 

  • Dubois, E. A., Kam, K. L., Somsen, G. A., Boer, G. J., de Bruin, K., Batink, H. D., et al. (1996). Cardiac iodine-123 metaiodobenzylguanidine uptake in animals with diabetes mellitus and/or hypertension. European Journal of Nuclear Medicine, 23, 901–908. doi:10.1007/BF01084363.

    Article  PubMed  CAS  Google Scholar 

  • Edwards, E., King, J. A., & Fray, J. (2000). Hypertension and insulin resistant models have divergent propensities to learned helpless behavior in rodents. American Journal of Hypertension, 13, 659–665. doi:10.1016/S0895-7061(99)00271-X.

    Article  PubMed  CAS  Google Scholar 

  • Esler, M., Julius, S., Zweifler, A., Randall, O., Harburg, E., Gardiner, H., et al. (1977). Mild high-renin essential hypertension. Neurogenic human hypertension? The New England Journal of Medicine, 296, 405–411.

    PubMed  CAS  Google Scholar 

  • Fang, Z., Carlson, S. H., Peng, N., & Wyss, J. M. (2000). Circadian rhythm of plasma sodium is disrupted in spontaneously hypertensive rats fed a high-NaCl diet. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 278, R1490–R1495.

    PubMed  CAS  Google Scholar 

  • Fukunaga, K., & Miyamoto, E. (2000). A working model of CaM kinase II activity in hippocampal long-term potentiation and memory. Neuroscience Research, 38, 3–17. doi:10.1016/S0168-0102(00)00139-5.

    Article  PubMed  CAS  Google Scholar 

  • Fukunaga, K., Muller, D., & Miyamoto, E. (1996). CaM kinase II in long-term potentiation. Neurochemistry International, 28, 343–358. doi:10.1016/0197-0186(95)00097-6.

    Article  PubMed  CAS  Google Scholar 

  • Gerges, N. Z., Aleisa, A. M., Alhaider, A. A., & Alkadhi, K. A. (2002). Reduction of elevated arterial blood pressure in obese Zucker rats by inhibition of ganglionic long-term potentiation. Neuropharmacology, 43, 1070–1076. doi:10.1016/S0028-3908(02)00283-6.

    Article  PubMed  CAS  Google Scholar 

  • Gerges, N. Z., Aleisa, A. M., Schwarz, L. A., & Alkadhi, K. A. (2003). Chronic psychosocial stress decreases calcineurin in the dentate gyrus: a possible mechanism for preservation of early ltp. Neuroscience, 117, 869–874. doi:10.1016/S0306-4522(02)00766-2.

    Article  PubMed  CAS  Google Scholar 

  • Gerges, N. Z., Aleisa, A. M., Schwarz, L. A., & Alkadhi, K. A. (2004). Reduced basal CaMKII levels in hippocampal CA1 region: possible cause of stress-induced impairment of LTP in chronically stressed rats. Hippocampus, 14, 402–410. doi:10.1002/hipo.10193.

    Article  PubMed  CAS  Google Scholar 

  • Giese, K. P., Fedorov, N. B., Filipkowski, R. K., & Silva, A. J. (1998). Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science, 279, 870–873. doi:10.1126/science.279.5352.870.

    Article  PubMed  CAS  Google Scholar 

  • Hadjiconstantinou, M., Potter, P. E., & Neff, N. H. (1982). Trans-synaptic modulation via muscarinic receptors of serotonin-containing small intensely fluorescent cells of superior cervical ganglion. The Journal of Neuroscience, 2, 1836–1839.

    PubMed  CAS  Google Scholar 

  • Hogan, Y. H., Hawkins, R., & Alkadhi, K. A. (1998). Adenosine A1 receptor activation inhibits LTP in sympathetic ganglia. Brain Research, 807, 19–28. doi:10.1016/S0006-8993(98)00694-5.

    Article  PubMed  CAS  Google Scholar 

  • Ikegaya, Y., Saito, H., & Matsuki, N. (1994). Involvement of carbon monoxide in long-term potentiation in the dentate gyrus of anesthetized rats. Japanese Journal of Pharmacology, 64, 225–227. doi:10.1254/jjp.64.225.

    Article  PubMed  CAS  Google Scholar 

  • Kandel, E. R., & Hawkins, R. D. (1992). The biological basis of learning and individuality. Scientific American, 267, 78–86.

    Article  PubMed  CAS  Google Scholar 

  • Kasiske, B. L., O’Donnell, M. P., & Keane, W. F. (1992). The Zucker rat model of obesity, insulin resistance, hyperlipidemia, and renal injury. Hypertension, 19, I110–I115.

    PubMed  CAS  Google Scholar 

  • Kurtz, T. W., Morris, R. C., & Pershadsingh, H. A. (1989). The Zucker fatty rat as a genetic model of obesity and hypertension. Hypertension, 13, 896–901.

    PubMed  CAS  Google Scholar 

  • Landsberg, L., & Young, J. B. (1985). Insulin-mediated glucose metabolism in the relationship between dietary intake and sympathetic nervous system activity. International Journal of Obesity, 9(Suppl 2), 63–68.

    PubMed  CAS  Google Scholar 

  • Lin, Y. Q., & Bennett, M. R. (1994). Nitric oxide modulation of quantal secretion in chick ciliary ganglia. The Journal of Physiology, 481(Pt 2), 385–394.

    PubMed  CAS  Google Scholar 

  • Lledo, P. M., Hjelmstad, G. O., Mukherji, S., Soderling, T. R., Malenka, R. C., & Nicoll, R. A. (1995). Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. Proceedings of the National Academy of Sciences of the United States of America, 92, 11175–11179. doi:10.1073/pnas.92.24.11175.

    Article  PubMed  CAS  Google Scholar 

  • Macor, J. E., Gurley, D., Lanthorn, T., Loch, J., Mack, R. A., Mullen, G., et al. (2001). The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist. Bioorganic and Medicinal Chemistry Letters, 11, 319–321.

    Article  PubMed  CAS  Google Scholar 

  • Malenka, R. C., Kauer, J. A., Perkel, D. J., Mauk, M. D., Kelly, P. T., Nicoll, R. A., et al. (1989). An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature, 340, 554–557. doi:10.1038/340554a0.

    Article  PubMed  CAS  Google Scholar 

  • Marwaha, A., Banday, A. A., & Lokhandwala, M. F. (2004). Reduced renal dopamine D1 receptor function in streptozotocin-induced diabetic rats. American Journal of Physiology. Renal Physiology, 286, F451–457.

    Article  PubMed  CAS  Google Scholar 

  • Maurice, D. H., & Haslam, R. J. (1990). Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: Inhibition of cyclic AMP breakdown by cyclic GMP. Molecular Pharmacology, 37, 671–681.

    PubMed  CAS  Google Scholar 

  • McEwen, B. S. (1998). Protective and damaging effects of stress mediators. The New England Journal of Medicine, 338, 171–179. doi:10.1056/NEJM199801153380307.

    Article  PubMed  CAS  Google Scholar 

  • Medina, J. H., & Izquierdo, I. (1995). Retrograde messengers, long-term potentiation and memory Brain Research. Brain Research Reviews, 21, 185–194.

    Article  PubMed  CAS  Google Scholar 

  • Minota, S., Kumamoto, E., Kitakoga, O., & Kuba, K. (1991). Long-term potentiation induced by a sustained rise in the intraterminal Ca2+ in bull-frog sympathetic ganglia. The Journal of Physiology, 435, 421–438.

    PubMed  CAS  Google Scholar 

  • Morgan, D. A., Anderson, E. A., & Mark, A. L. (1995). Renal sympathetic nerve activity is increased in obese Zucker rats. Hypertension, 25, 834–838.

    PubMed  CAS  Google Scholar 

  • Nichols, R. A., & Mollard, P. (1996). Direct observation of serotonin 5-HT3 receptor-induced increases in calcium levels in individual brain nerve terminals. Journal of Neurochemistry, 67, 581–592.

    Article  PubMed  CAS  Google Scholar 

  • Pacak, K., Palkovits, M., Makino, S., Kopin, I. J., & Goldstein, D. S. (1996). Brainstem hemisection decreases corticotropin-releasing hormone mRNA in the paraventricular nucleus but not in the central amygdaloid nucleus. Journal of Neuroendocrinology, 8, 543–551. doi:10.1046/j.1365-2826.1996.04888.x.

    Article  PubMed  CAS  Google Scholar 

  • Pamidimukkala, J., & Jandhyala, B. S. (1996). Evaluation of hemodynamics, vascular reactivity and baroreceptor compensation in the insulin resistant Zucker obese rats. Clin Exp Hypertens, 18, 1089–1104. doi:10.3109/10641969609081036.

    Article  PubMed  CAS  Google Scholar 

  • Papke, R. L., Porter Papke, J. K., & Rose, G. M. (2004). Activity of alpha7-selective agonists at nicotinic and serotonin 5HT3 receptors expressed in Xenopus oocytes. Bioorganic and Medicinal Chemistry Letters, 14, 1849–1853.

    Article  PubMed  CAS  Google Scholar 

  • Papke, R. L., Schiff, H. C., Jack, B. A., & Horenstein, N. A. (2005). Molecular dissection of tropisetron, an alpha7 nicotinic acetylcholine receptor-selective partial agonist. Neuroscience Letters, 378, 140–144.

    Article  PubMed  CAS  Google Scholar 

  • Pettit, D. L., Perlman, S., & Malinow, R. (1994). Potentiated transmission and prevention of further LTP by increased CaMKII activity in postsynaptic hippocampal slice neurons. Science, 266, 1881–1885. doi:10.1126/science.7997883.

    Article  PubMed  CAS  Google Scholar 

  • Poss, K. D., Thomas, M. J., Ebralidze, A. K., O’Dell, T. J., & Tonegawa, S. (1995). Hippocampal long-term potentiation is normal in heme oxygenase-2 mutant mice. Neuron, 15, 867–873. doi:10.1016/0896-6273(95)90177-9.

    Article  PubMed  CAS  Google Scholar 

  • Reaven, G. M., Lithell, H., & Landsberg, L. (1996). Hypertension and associated metabolic abnormalities—The role of insulin resistance and the sympathoadrenal system. The New England Journal of Medicine, 334, 374–381. doi:10.1056/NEJM199602083340607.

    Article  PubMed  CAS  Google Scholar 

  • Roberts, L. A., Large, C. H., Higgins, M. J., Stone, T. W., O’Shaughnessy, C. T., & Morris, B. J. (1998). Increased expression of dendritic mRNA following the induction of long-term potentiation. Brain Research. Molecular Brain Research, 56, 38–44. doi:10.1016/S0169-328X(98)00026-6.

    Article  PubMed  CAS  Google Scholar 

  • Scott, T. R., & Bennett, M. R. (1993). The effect of nitric oxide on the efficacy of synaptic transmission through the chick ciliary ganglion. British Journal of Pharmacology, 110, 627–632.

    PubMed  CAS  Google Scholar 

  • Schuman, E. M., & Madison, D. V. (1994). Locally distributed synaptic potentiation in the hippocampus. Science, 263, 532–536.

    Article  PubMed  CAS  Google Scholar 

  • Sheng, H., Gagne, G. D., Matsumoto, T., Miller, M. F., Forstermann, U., & Murad, F. (1993). Nitric oxide synthase in bovine superior cervical ganglion. Journal of Neurochemistry, 61, 1120–1126. doi:10.1111/j.1471-4159.1993.tb03628.x.

    Article  PubMed  CAS  Google Scholar 

  • Siegrist, J. (2001). Psychosocial factors influencing development and course of coronary heart disease. Herz, 26, 316–325. doi:10.1007/PL00002036.

    Article  PubMed  CAS  Google Scholar 

  • Stevens, C. F., & Wang, Y. (1993). Reversal of long-term potentiation by inhibitors of haem oxygenase. Nature, 364, 147–149. doi:10.1038/364147a0.

    Article  PubMed  CAS  Google Scholar 

  • Suter, P. M., Maire, R., Holtz, D., & Vetter, W. (1997). Relationship between self-perceived stress and blood pressure. Journal of Human Hypertension, 11, 171–176. doi:10.1038/sj.jhh.1000409.

    Article  PubMed  CAS  Google Scholar 

  • Thomas, K. L., Laroche, S., Errington, M. L., Bliss, T. V., & Hunt, S. P. (1994). Spatial and temporal changes in signal transduction pathways during LTP. Neuron, 13, 737–745. doi:10.1016/0896-6273(94)90040-X.

    Article  PubMed  CAS  Google Scholar 

  • Tonello, C., Giordano, A., Cozzi, V., Cinti, S., Stock, M. J., Carruba, M. O., et al. (1999). Role of sympathetic activity in controlling the expression of vascular endothelial growth factor in brown fat cells of lean and genetically obese rats. FEBS Letters, 442, 167–172. doi:10.1016/S0014-5793(98)01627-5.

    Article  PubMed  CAS  Google Scholar 

  • Turner, N. C., Gudgeon, C., & Toseland, N. (1995). Effects of genetic hyperinsulinaemia on vascular reactivity, blood pressure, and renal structure in the Zucker rat. Journal of Cardiovascular Pharmacology, 26, 714–720. doi:10.1097/00005344-199511000-00007.

    Article  PubMed  CAS  Google Scholar 

  • Van Zwieten, P. A., Kam, K. L., Pijl, A. J., Hendriks, M. G., Beenen, O. H., & Pfaffendorf, M. (1996). Hypertensive diabetic rats in pharmacological studies. Pharmacological Research, 33, 95–105. doi:10.1006/phrs.1996.0015.

    Article  PubMed  Google Scholar 

  • Walker, B. R., & Edwards, C. R. (1994). New mechanisms for corticosteroid-induced hypertension. British Medical Bulletin, 50, 342–355.

    PubMed  CAS  Google Scholar 

  • Walker, C. D., Scribner, K. A., Stern, J. S., & Dallman, M. F. (1992). Obese Zucker (fa/fa) rats exhibit normal target sensitivity to corticosterone and increased drive to adrenocorticotropin during the diurnal trough. Endocrinology, 131, 2629–2637. doi:10.1210/en.131.6.2629.

    Article  PubMed  CAS  Google Scholar 

  • Wang, J. H., & Kelly, P. T. (1996). The balance between postsynaptic Ca(2+)-dependent protein kinase and phosphatase activities controlling synaptic strength. Learning & Memory (Cold Spring Harbor, N.Y.), 3, 170–181. doi:10.1101/lm.3.2-3.170.

    CAS  Google Scholar 

  • Zhuo, M., Small, S. A., Kandel, E. R., & Hawkins, R. D. (1993). Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus. Science, 260, 1946–1950. doi:10.1126/science.8100368.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

Support is contributed by a grant (0255402Y) from AHA-Texas Affiliate.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to K. A. Alkadhi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alzoubi, K.H., Aleisa, A.M. & Alkadhi, K.A. Expression of gLTP in Sympathetic Ganglia of Obese Zucker Rats In Vivo: Molecular Evidence. J Mol Neurosci 35, 297–306 (2008). https://doi.org/10.1007/s12031-008-9110-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-008-9110-6

Keywords

Navigation