Hostname: page-component-8448b6f56d-cfpbc Total loading time: 0 Render date: 2024-04-19T21:39:01.166Z Has data issue: false hasContentIssue false
  • English
  • Français

GPI-1046 Increases Presenilin-1 Expression and Restores NMDA Channel Activity

Published online by Cambridge University Press:  02 December 2014

Joseph P. Steiner ,
Kathryn B. Payne ,
Christopher Drummond Main ,
Sabrina D'Alfonso ,
Kirsten X. Jacobsen ,
T. Philip Hicks ,
William A. Staines  and
Michael O. Poulter
Joseph P. Steiner
Affiliation:
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Kathryn B. Payne
Affiliation:
Neuroscience Research Institute, Department of Psychology, Carleton University
Christopher Drummond Main
Affiliation:
Neuroscience Research Institute, Department of Psychology, Carleton University
Sabrina D'Alfonso
Affiliation:
Neuroscience Research Institute, Department of Psychology, Carleton University
Kirsten X. Jacobsen
Affiliation:
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa
T. Philip Hicks
Affiliation:
Department of Biology and Faculty of Graduate Studies, Lakehead University, Thunder Bay
William A. Staines
Affiliation:
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa
Michael O. Poulter*
Affiliation:
Neuroscience Research Institute, Department of Psychology, Carleton University
*
Molecular Brain Research Group, Robarts Research Institute, 100 Perth Drive Box 5015, London Ontario, N6A 5K8, Canada
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
Background:

Previously we showed that 6-hydroxydopamine lesions of the substantia nigra eliminate corticostriatal LTP and that the neuroimmunolophilin ligand (NIL), GPI-1046, restores LTP.

Methods:

We used cDNA microarrays to determine what mRNAs may be over- or under-expressed in response to lesioning and/or GPI-1046 treatment. Patch clamp recordings were performed to investigate changes in NMDA channel function before and after treatments.

Results:

We found that 51 gene products were differentially expressed. Among these we found that GPI-1046 treatment up-regulated presenilin-1 (PS-1) mRNA abundance. This finding was confirmed using QPCR. PS-1 protein was also shown to be over-expressed in the striatum of lesioned/GPI-1046-treated rats. As PS-1 has been implicated in controlling NMDA-receptor function and LTP is reduced by lesioning we assayed NMDA mediated synaptic activity in striatal brain slices. The lesion-induced reduction of dopaminergic innervation was accompanied by the near complete loss of NDMA receptor-mediated synaptic transmission between the cortex and striatum. GPI-1046 treatment of the lesioned rats restored NMDA-mediated synaptic transmission but not the dopaminergic innervation. Restoration of NDMA channel function was apparently specific as the sodium channel current density was also reduced due to lesioning but GPI-1046 did not reverse this effect. We also found that restoration of NMDA receptor function was also not associated with either an increase in NMDA receptor mRNA or protein expression.

Conclusion:

As it has been previously shown that PS-1 is critical for normal NMDA receptor function, our data suggest that the improvement of excitatory neurotransmission occurs through the GPI-1046-induced up-regulation of PS-1.

Type
Original Article
Information
Canadian Journal of Neurological Sciences , Volume 37 , Issue 4 , July 2010 , pp. 457 - 467
Copyright
Copyright © The Canadian Journal of Neurological 2010

References

1. Ross, DT, Guo, H, Howorth, P, Chen, Y, Hamilton, GS, Steiner, JP. The small molecule FKBP ligand GPI 1046 induces partial striatal re-innervation after intranigral 6-hydroxydopamine lesion in rats. Neurosci Lett. 2001; 920: 113–6.CrossRefGoogle Scholar
2. Steiner, JP, Hamilton, GS, Ross, DT, Valentine, HL, Guo, H, Connolly, MA, et al. Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc Natl Acad Sci. USA. 1997; 94: 2019–24.Google Scholar
3. Zhang, C, Steiner, JP, Hamilton, GS, Hicks, TP, Poulter, MO. Regeneration of dopaminergic function in 6-hydroxydopamine-lesioned rats by neuroimmunophilin ligand treatment. J Neurosci. 2001; 21: RC156.Google Scholar
4. Sauer, H, Francis, JM, Jiang, H, Hamilton, GS, Steiner, JP. Systemic treatment with GPI 1046 improves spatial memory and reverses cholinergic neuron atrophy in the medial septal nucleus of aged mice. Brain Res. 1999; 842: 109–18.CrossRefGoogle ScholarPubMed
5. Bavetta, S, Hamlyn, PJ, Burnstock, G, Lieberman, AR, Anderson, PN. The effects of FK506 on dorsal column axons following spinal cord injury in adult rats: neuroprotection and local regeneration. Exp Neurol. 1999; 158: 382–93.Google Scholar
6. Campbell, G, Holt, JK, Shotton, HR, Anderson, PN, Bavetta, S, Lieberman, AR. Spontaneous axonal regeneration after optic nerve injury in adult rat. NeuroReport. 1999; 1910: 3955–60.Google Scholar
7. Garcia-Criado, FJ, Palma-Vargas, JM, Valdunciel-Garcia, JJ, Toledo, AH, Misawa, K, Gomez-Alonso, A, et al. Tacrolimus (FK506) down-regulates free radical tissue levels, serum cytokines, and neutrophil infiltration after severe liver ischemia. Transplantation. 1997; 64: 594–8.Google Scholar
8. Gold, BG, Zeleny-Pooley, M, Chaturvedi, P, Wang, MS. Oral administration of a nonimmunosuppressant FKBP-12 ligand speeds nerve regeneration. NeuroReport. 1998; 9: 553–8.Google Scholar
9. Kupina, NC, Detloff, MR, Dutta, S, Hall, ED. Neuroimmunophilin ligand V-10,367 is neuroprotective after 24-hour delayed administration in a mouse model of diffuse traumatic brain injury. J Cereb Blood Flow Metab. 2002; 1922; 1212–21.Google Scholar
10. Matsuda, T, Yamaguchi, Y, Matsumura, F, Akizuki, E, Okabe, K, Liang, J, et al. Immunosuppressants decrease neutrophil chemo-attractant and attenuate ischemia/reperfusion injury of the liver in rats. J Trauma. 1998; 44: 475–84.CrossRefGoogle Scholar
11. Nishinaka, Y, Sugiyama, S, Yokota, M, Saito, H, Ozawa, T. Protective effect of FK506 on ischemia/reperfusion-induced myocardial damage in canine heart. J Cardiovasc Pharmacol. 1993; 21: 448–54.Google Scholar
12. Sezen, SF, Hoke, A, Burnett, AL, Snyder, SH. Immunophilin ligand FK506 is neuroprotective for penile innervation. Nat Med. 2001 7; 1073–4.Google Scholar
13. Sezen, SF, Blackshaw, S, Steiner, JP, Burnett, AL. FK506 binding protein 12 is expressed in rat penile innervation and upregulated after cavernous nerve injury. Int J Impot Res. 2002; 14: 506–12.Google Scholar
14. Suehiro, E, Singleton, RH, Stone, JR, Povlishock, JT. The immunophilin ligand FK506 attenuates the axonal damage associated with rapid rewarming following posttraumatic hypothermia. Exp Neurol. 2001; 199-210.CrossRefGoogle Scholar
15. Sakr, M, Zetti, G, McClain, C, Gavaler, J, Nalesnik, M, Todo, S, et al. The protective effect of FK506 pretreatment against renal ischemia/reperfusion injury in rats. Transplantation. 1992; 53: 987–91.Google Scholar
16. Keep, MF, Uchino, H, Elmer, E. Introduction: Immunosuppressants as neuroprotective agents. In: Borlongan, CV, Isacson, O, Sanberg, PR, editors. Immunosuppressant analogs in neuroprotection. Totowa, NJ: Humana Press Inc.; 2003. p. 3–32.Google Scholar
17. Steiner, JP, Connolly, MA, Valentine, HL, Hamilton, GS, Dawson, TM, Hester, L, et al. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A. Nat Med. 1997; 3: 421–8.Google Scholar
18. Liu, J, Farmer, JD Jr, Lane, WS, Friedman, J, Weissman, I, Schreiber, SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991; 66: 807–15.CrossRefGoogle ScholarPubMed
19. Poulter, MO, Payne, KB, Steiner, JP. Neuroimmunophilins: a novel drug therapy for the reversal of neurodegenerative disease? Neurosci. 2004; 128: 1–6.Google Scholar
20. Yang, YH, Speed, T. Design of micorarray expression experiemnts. In: Bowtell, D, Sambrook, J, editors. DNA microarrays. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2003. p. 513–25.Google Scholar
21. Meguro, R, Lu, ZW, Gavrilovici, C, Poulter, MO. Static, transient and permanent organisation of GABAA receptor expression in calbindin positive interneurons in response to amygdala kindled seizures. J Neurochem. 2004; 91: 144–54.Google Scholar
22. McIntyre, DC, Hutcheon, B, Schwabe, K, Poulter, MO. Divergent GABA(A) receptor-mediated synaptic transmission in genetically seizure-prone and seizure-resistant rats. J Neurosci. 2002; 22: 9922–31.Google Scholar
23. Saura, CA, Choi, SY, Beglopoulos, V, Malkani, S, Zhang, D, Shankaranarayana Rao, BS, et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron. 2004; 42: 23–36.Google Scholar
24. Nestler, EJ. Under siege: the brain on opiates. Neuron. 1996; 16: 897–900.Google Scholar
25. Calabresi, P, Saiardi, A, Pisani, A, Baik, JH, Centonze, D, Mercuri, NB, et al. Abnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors. J Neurosci. 1997; 17: 4536–44.Google Scholar
26. Berke, JD, Hyman, SE. Addiction, dopamine, and the molecular mechanisms of memory. Neuron. 2000; 25: 515–32.Google Scholar
27. Lai, SK, Tse, YC, Yang, MS, Wong, CK, Chan, YS, Yung, KK. Gene expression of glutamate receptors GluR1 and NR1 is differentially modulated in striatal neurons in rats after 6-hydroxydopamine lesion. Neurochem Int. 2003; 43: 639–53.Google Scholar
28. Dunah, AW, Standaert, DG. Subcellular segregation of distinct heteromeric NMDA glutamate receptors in the striatum. J Neurochem. 2003; 85: 935–43.Google Scholar
29. Fan, XD, Li, XM, Ashe, PC, Juorio, AV. Lesion of the substantia nigra pars compacta downregulates striatal glutamate receptor subunit mRNA expression. Brain Res. 1999; 850: 79–86.Google Scholar
30. Calabresi, P, Gubellini, P, Centonze, D, Picconi, B, Bernardi, G, Chergui, K, et al. Dopamine and cAMP-regulated phosphoprotein 32 kDa controls both striatal long-term depression and long-term potentiation, opposing forms of synaptic plasticity. J Neurosci. 2000; 20: 8443–51.Google Scholar
31. Crump, FT, Dillman, KS, Craig, AM. cAMP-dependent protein kinase mediates activity-regulated synaptic targeting of NMDA receptors. J Neurosci. 2001; 21: 5079–88.Google Scholar
32. Thinakaran, G, Parent, AT. Identification of the role of presenilins beyond Alzheimer’s disease. Pharmacol Res. 2004; 50: 411–18.Google Scholar
33. Zhang, C, Wu, B, Beglopoulos, V, Wines-Samuelson, M, Zhang, D, Dragatsis, I, et al. Presenilins are essential for regulating neurotransmitter release. Nature. 2009; 460: 632–6.Google Scholar
34. Edlich, F, Weiwad, M, Erdmann, F, Fanghanel, J, Jarczowski, F, Rahfeld, JU, et al. Bcl-2 regulator FKBP38 is activated by Ca(2+)/calmodulin. EMBO J. 2005; 20; 2688–99.Google Scholar
35. Gold, BG, Densmore, V, Shou, W, Matzuk, MM, Gordon, HS. Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506. J Pharmacol Exp Ther. 1999; 289: 1202–10.Google Scholar
36. Berezikov, E, Guryev, V, Cuppen, E. CONREAL web server: identification and visualization of conserved transcription factor binding sites. Nucleic Acids Res. 2005; 33; W447–50.Google Scholar
37. Berezikov, E, Guryev, V, Plasterk, RH, Cuppen, E. CONREAL: conserved regulatory elements anchored alignment algorithm for identification of transcription factor binding sites by phylogenetic footprinting. Genome Res. 2004; 14: 170–8.Google Scholar
38. Marjaux, E, Hartmann, D, De Strooper, B. Presenilins in memory, Alzheimer’s disease, and therapy. Neuron. 2004; 42: 189–92.Google Scholar
39. Selkoe, DJ. Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol. 2004; 6: 1054–61.Google Scholar
40. Takao, M, Ghetti, B, Hayakawa, I, Ikeda, E, Fukuuchi, Y, Miravalle, L, et al. A novel mutation (G217D) in the Presenilin 1 gene (PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum. Acta Neuropathol. 2002; 104: 155–70.Google Scholar
41. Page, K, Hollister, R, Tanzi, RE, Hyman, BT. In situ hybridization analysis of presenilin 1 mRNA in Alzheimer disease and in lesioned rat brain. Proc Natl Acad Sci USA. 1996; 93: 14020–4.Google Scholar
42. Donoviel, DB, Hadjantonakis, AK, Ikeda, M, Zheng, H, Hyslop, PS, Bernstein, A. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 1999; 13: 2801–10.Google Scholar
43. Bursztajn, S, DeSouza, R, McPhie, DL, Berman, SA, Shioi, J, Robakis, NK, et al. Overexpression in neurons of human presenilin-1 or a presenilin-1 familial Alzheimer disease mutant does not enhance apoptosis. J Neurosci. 1998; 18: 9790–9.Google Scholar
44. Wen, PH, Shao, X, Shao, Z, Hof, PR, Wisniewski, T, Kelley, K, et al. Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice. Neurobiol Dis. 2002; 10: 8–19.Google Scholar
45. Zhang, W, Jin, HW, Wang, XL. Effects of presenilins and beta-amyloid precursor protein on delayed rectifier potassium channels in cultured rat hippocampal neurons. Acta Pharmacol Sin. 2004; 25: 181–5.Google Scholar
46. Periz, G, Fortini, ME. Functional reconstitution of gamma-secretase through coordinated expression of presenilin, nicastrin, Aph-1, and Pen-2. J Neurosci Res. 2004; 77: 309–22.Google Scholar