Epilepsy in a melanocyte-lineage mTOR hyperactivation mouse model: A novel epilepsy model
Autoři:
Fei Yang aff001; Lingli Yang aff001; Mari Wataya-Kaneda aff001; Lanting Teng aff001; Ichiro Katayama aff001
Působiště autorů:
Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
aff001
Vyšlo v časopise:
PLoS ONE 15(1)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0228204
Souhrn
Objective
To clarify the complex mechanism underlying epileptogeneis, a novel animal model was generated.
Methods
In our previous research, we have generated a melanocyte-lineage mTOR hyperactivation mouse model (Mitf-M-Cre Tsc2 KO mice; cKO mice) to investigate mTOR pathway in melanogenesis regulation, markedly reduced skin pigmentation was observed. Very unexpectedly, spontaneous recurrent epilepsy was also developed in this mouse model.
Results
Compared with control littermates, no change was found in either brain size or brain mass in cKO mice. Hematoxylin staining revealed no obvious aberrant histologic features in the whole brains of cKO mice. Histoimmunofluorescence staining and electron microscopy examination revealed markedly increased mTOR signaling and hyperproliferation of mitochondria in cKO mice, especially in the hippocampus. Furthermore, rapamycin treatment reversed these abnormalities.
Conclusions
This study suggests that our melanocyte-lineage mTOR hyperactivation mouse is a novel animal model of epilepsy, which may promote the progress of both epilepsy and neurophysiology research.
Klíčová slova:
Cerebral cortex – Epilepsy – Hippocampus – Mitochondria – Mouse models – Neuronal dendrites – Neurons – Pyramidal cells
Zdroje
1. Singh A, Trevick S. The Epidemiology of Global Epilepsy. Neurol Clin. 2016;34(4):837–47. Epub 2016/10/11. S0733-8619(16)30037-8 [pii] doi: 10.1016/j.ncl.2016.06.015 27719996.
2. Tachibana M. MITF: A stream flowing for pigment cells. Pigment Cell Research. 2000;13(4):230–40. doi: 10.1034/j.1600-0749.2000.130404.x ISI:000088714900003. 10952390
3. Markert CL, Silvers WK. The Effects of Genotype and Cell Environment on Melanoblast Differentiation in the House Mouse. Genetics. 1956;41(3):429–50. Epub 1956/05/01. 17247639; PubMed Central PMCID: PMC1209793.
4. Gudjohnsen SA, Atacho DA, Gesbert F, Raposo G, Hurbain I, Larue L, et al. Meningeal Melanocytes in the Mouse: Distribution and Dependence on Mitf. Frontiers in Neuroanatomy. 2015;9:149. Epub 2015/12/05. doi: 10.3389/fnana.2015.00149 26635543; PubMed Central PMCID: PMC4658736.
5. Barden H, Levine S. Histochemical observations on rodent brain melanin. Brain Res Bull. 1983;10(6):847–51. Epub 1983/06/01. 0361-9230(83)90218-6 [pii]. doi: 10.1016/0361-9230(83)90218-6 6616275.
6. Goldgeier MH, Klein LE, Klein-Angerer S, Moellmann G, Nordlund JJ. The distribution of melanocytes in the leptomeninges of the human brain. The Journal of investigative dermatology. 1984;82(3):235–8. Epub 1984/03/01. doi: 10.1111/1523-1747.ep12260111 6699426.
7. Yaar M, Park HY. Melanocytes: a window into the nervous system. The Journal of investigative dermatology. 2012;132(3 Pt 2):835–45. Epub 2011/12/14. doi: 10.1038/jid.2011.386 22158549.
8. Cross JH. Neurocutaneous syndromes and epilepsy-issues in diagnosis and management. Epilepsia. 2005;46 Suppl 10:17–23. Epub 2005/12/20. doi: 10.1111/j.1528-1167.2005.00353.x 16359466.
9. Yang F, Yang L, Wataya-Kaneda M, Yoshimura T, Tanemura A, Katayama I. Uncoupling of ER/Mitochondrial Oxidative Stress in mTORC1 Hyperactivation-Associated Skin Hypopigmentation. J Invest Dermatol. 2018;138(3):669–78. Epub 2017/10/31. S0022-202X(17)33070-1 [pii] doi: 10.1016/j.jid.2017.10.007 29080681.
10. Kaur S, Pedersen NP, Yokota S, Hur EE, Fuller PM, Lazarus M, et al. Glutamatergic signaling from the parabrachial nucleus plays a critical role in hypercapnic arousal. J Neurosci. 2013;33(18):7627–40. Epub 2013/05/03. doi: 10.1523/JNEUROSCI.0173-13.2013 33/18/7627 [pii]. 23637157; PubMed Central PMCID: PMC3674488.
11. Sloviter RS. A simplified timm stain procedure compatible with formaldehyde fixation and routine paraffin embedding of rat brain. Brain Research Bulletin. 1982;8(6):771–4. doi: 10.1016/0361-9230(82)90104-6 6182964
12. Opitz-Araya X, Barria A. Organotypic hippocampal slice cultures. Journal of visualized experiments: JoVE. 2011;(48). Epub 2011/02/23. doi: 10.3791/2462 21339716; PubMed Central PMCID: PMC3197400.
13. Brewer GJ, Torricelli JR. Isolation and culture of adult neurons and neurospheres. Nature protocols. 2007;2(6):1490–8. Epub 2007/06/05. doi: 10.1038/nprot.2007.207 17545985.
14. Sasaki T, Takahashi N, Matsuki N, Ikegaya Y. Fast and accurate detection of action potentials from somatic calcium fluctuations. J Neurophysiol. 2008;100(3):1668–76. Epub 2008/07/04. doi: 10.1152/jn.00084.2008 [pii]. 18596182.
15. Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science (New York, NY). 2001;294(5549):2186–9. Epub 2001/11/03. doi: 10.1126/science.1065518 11691952.
16. Marino S, Krimpenfort P, Leung C, van der Korput HAGM, Trapman J, Camenisch I, et al. PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum. Development. 2002;129(14):3513–22. 12091320
17. Fraser MM, Zhu X, Kwon C-H, Uhlmann EJ, Gutmann DH, Baker SJ. Pten Loss Causes Hypertrophy and Increased Proliferation of Astrocytes In vivo. Cancer research. 2004;64(21):7773–9. doi: 10.1158/0008-5472.CAN-04-2487 15520182
18. Yue Q, Groszer M, Gil JS, Berk AJ, Messing A, Wu H, et al. PTEN deletion in Bergmann glia leads to premature differentiation and affects laminar organization. Development. 2005;132(14):3281–91. doi: 10.1242/dev.01891 15944184
19. Ling-Hui Z, Lin X, GD H., Michael W. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Annals of neurology. 2008;63(4):444–53. doi: 10.1002/ana.21331 18389497
20. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, et al. Pten regulates neuronal arborization and social interaction in mice. Neuron. 2006;50(3):377–88. Epub 2006/05/06. doi: 10.1016/j.neuron.2006.03.023 16675393; PubMed Central PMCID: PMC3902853.
21. Kwiatkowski DJ. Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer biology & therapy. 2003;2(5):471–6. Epub 2003/11/14. doi: 10.4161/cbt.2.5.446 14614311.
22. Kwiatkowski DJ. Tuberous sclerosis: from tubers to mTOR. Annals of human genetics. 2003;67(Pt 1):87–96. Epub 2003/01/31. doi: 10.1046/j.1469-1809.2003.00012.x 12556239.
23. Bullitt E. Expression of c-fos-like protein as a marker for neuronal activity following noxious stimulation in the rat. The Journal of comparative neurology. 1990;296(4):517–30. Epub 1990/06/22. doi: 10.1002/cne.902960402 2113539.
24. Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL. Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron. 2013;78(3):510–22. Epub 2013/05/15. doi: 10.1016/j.neuron.2013.03.017 23664616; PubMed Central PMCID: PMC3690324.
25. de Curtis M, Avoli M. GABAergic networks jump-start focal seizures. Epilepsia. 2016;57(5):679–87. Epub 2016/04/12. doi: 10.1111/epi.13370 27061793; PubMed Central PMCID: PMC4878883.
26. Khoshkhoo S, Vogt D, Sohal VS. Dynamic, Cell-Type-Specific Roles for GABAergic Interneurons in a Mouse Model of Optogenetically Inducible Seizures. Neuron. 2017;93(2):291–8. Epub 2017/01/04. doi: 10.1016/j.neuron.2016.11.043 28041880; PubMed Central PMCID: PMC5268075.
27. Lucchi C, Costa AM, Giordano C, Curia G, Piat M, Leo G, et al. Involvement of PPARgamma in the Anticonvulsant Activity of EP-80317, a Ghrelin Receptor Antagonist. Front Pharmacol. 2017;8:676. Epub 2017/10/12. doi: 10.3389/fphar.2017.00676 29018345; PubMed Central PMCID: PMC5614981.
28. Sutula T, Cascino G, Cavazos J, Parada I, Ramirez L. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Annals of neurology. 1989;26(3):321–30. Epub 1989/09/01. doi: 10.1002/ana.410260303 2508534.
29. Pun RY, Rolle IJ, Lasarge CL, Hosford BE, Rosen JM, Uhl JD, et al. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron. 2012;75(6):1022–34. Epub 2012/09/25. doi: 10.1016/j.neuron.2012.08.002 22998871; PubMed Central PMCID: PMC3474536.
30. Amiri A, Cho W, Zhou J, Birnbaum SG, Sinton CM, McKay RM, et al. Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2012;32(17):5880–90. Epub 2012/04/28. doi: 10.1523/jneurosci.5462-11.2012 22539849.
31. Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR, Leech JM, et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature. 2012;488(7413):647–51. Epub 2012/07/06. doi: 10.1038/nature11310 22763451; PubMed Central PMCID: PMC3615424.
32. Yang SB, Tien AC, Boddupalli G, Xu AW, Jan YN, Jan LY. Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons. Neuron. 2012;75(3):425–36. Epub 2012/08/14. doi: 10.1016/j.neuron.2012.03.043 22884327; PubMed Central PMCID: PMC3467009.
33. Schild D, Jung A, Schultens HA. Localization of calcium entry through calcium channels in olfactory receptor neurones using a laser scanning microscope and the calcium indicator dyes Fluo-3 and Fura-Red. Cell calcium. 1994;15(5):341–8. Epub 1994/05/01. doi: 10.1016/0143-4160(94)90009-4 8033192.
34. Jensen EC. Quantitative analysis of histological staining and fluorescence using ImageJ. Anat Rec (Hoboken). 2013;296(3):378–81. Epub 2013/02/06. doi: 10.1002/ar.22641 23382140.
35. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell metabolism. 2005;1(6):361–70. Epub 2005/08/02. doi: 10.1016/j.cmet.2005.05.004 16054085.
36. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450(7170):736–40. Epub 2007/11/30. doi: 10.1038/nature06322 18046414.
37. Schieke SM, Phillips D, McCoy JP Jr., Aponte AM, Shen RF, Balaban RS, et al. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. The Journal of biological chemistry. 2006;281(37):27643–52. Epub 2006/07/19. doi: 10.1074/jbc.M603536200 16847060.
38. Desai BN, Myers BR, Schreiber SL. FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(7):4319–24. Epub 2002/04/04. doi: 10.1073/pnas.261702698 11930000; PubMed Central PMCID: PMC123646.
39. Ramanathan A, Schreiber SL. Direct control of mitochondrial function by mTOR. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(52):22229–32. Epub 2010/01/19. doi: 10.1073/pnas.0912074106 20080789; PubMed Central PMCID: PMC2796909.
40. Morita M, Gravel SP, Chenard V, Sikstrom K, Zheng L, Alain T, et al. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell metabolism. 2013;18(5):698–711. Epub 2013/11/12. doi: 10.1016/j.cmet.2013.10.001 24206664.
41. Raab-Graham KF, Haddick PC, Jan YN, Jan LY. Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites. Science (New York, NY). 2006;314(5796):144–8. Epub 2006/10/07. doi: 10.1126/science.1131693 17023663.
42. Cudmore RH, Fronzaroli-Molinieres L, Giraud P, Debanne D. Spike-time precision and network synchrony are controlled by the homeostatic regulation of the D-type potassium current. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2010;30(38):12885–95. Epub 2010/09/24. doi: 10.1523/jneurosci.0740-10.2010 20861392.
43. Metz AE, Spruston N, Martina M. Dendritic D-type potassium currents inhibit the spike afterdepolarization in rat hippocampal CA1 pyramidal neurons. The Journal of Physiology. 2007;581(Pt 1):175–87. doi: 10.1113/jphysiol.2006.127068 17317746; PubMed Central PMCID: PMC2075224.
44. Rho JM, Szot P, Tempel BL, Schwartzkroin PA. Developmental seizure susceptibility of kv1.1 potassium channel knockout mice. Developmental neuroscience. 1999;21(3–5):320–7. Epub 1999/11/27. doi: 10.1159/000017381 10575255.
45. Smart SL, Lopantsev V, Zhang CL, Robbins CA, Wang H, Chiu SY, et al. Deletion of the K(V)1.1 potassium channel causes epilepsy in mice. Neuron. 1998;20(4):809–19. Epub 1998/05/15. doi: 10.1016/s0896-6273(00)81018-1 9581771.
46. Robbins CA, Tempel BL. Kv1.1 and Kv1.2: similar channels, different seizure models. Epilepsia. 2012;53 Suppl 1:134–41. Epub 2012/05/25. doi: 10.1111/j.1528-1167.2012.03484.x 22612818.
47. Narayanan U, Nalavadi V, Nakamoto M, Thomas G, Ceman S, Bassell GJ, et al. S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade. The Journal of biological chemistry. 2008;283(27):18478–82. Epub 2008/05/14. doi: 10.1074/jbc.C800055200 18474609; PubMed Central PMCID: PMC2441545.
48. Lee CC, Huang CC, Wu MY, Hsu KS. Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. The Journal of biological chemistry. 2005;280(18):18543–50. Epub 2005/03/10. doi: 10.1074/jbc.M414112200 15755733.
49. Gong R, Park CS, Abbassi NR, Tang SJ. Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons. The Journal of biological chemistry. 2006;281(27):18802–15. Epub 2006/05/03. doi: 10.1074/jbc.M512524200 16651266.
50. Nimchinsky EA, Yasuda R, Oertner TG, Svoboda K. The Number of Glutamate Receptors Opened by Synaptic Stimulation in Single Hippocampal Spines. The Journal of Neuroscience. 2004;24(8):2054–64. doi: 10.1523/JNEUROSCI.5066-03.2004 14985448
51. Becker AJ. Review: Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesis. Neuropathol Appl Neurobiol. 2018;44(1):112–29. Epub 2017/11/14. doi: 10.1111/nan.12451 29130506.
52. Yutsudo N, Kamada T, Kajitani K, Nomaru H, Katogi A, Ohnishi YH, et al. fosB-null mice display impaired adult hippocampal neurogenesis and spontaneous epilepsy with depressive behavior. Neuropsychopharmacology. 2013;38(5):895–906. Epub 2013/01/11. doi: 10.1038/npp.2012.260 [pii]. 23303048; PubMed Central PMCID: PMC3672000.
53. Giordano C, Costa AM, Lucchi C, Leo G, Brunel L, Fehrentz JA, et al. Progressive Seizure Aggravation in the Repeated 6-Hz Corneal Stimulation Model Is Accompanied by Marked Increase in Hippocampal p-ERK1/2 Immunoreactivity in Neurons. Frontiers in Cellular Neuroscience. 2016;10:281. Epub 2016/12/27. doi: 10.3389/fncel.2016.00281 28018175; PubMed Central PMCID: PMC5159434.
54. Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, Sabatini BL. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nature neuroscience. 2005;8(12):1727–34. Epub 2005/11/16. doi: 10.1038/nn1566 16286931.
55. Kandratavicius L, Balista PA, Lopes-Aguiar C, Ruggiero RN, Umeoka EH, Garcia-Cairasco N, et al. Animal models of epilepsy: use and limitations. Neuropsychiatr Dis Treat. 2014;10:1693–705. Epub 2014/09/18. doi: 10.2147/NDT.S50371 [pii]. 25228809; PubMed Central PMCID: PMC4164293.
Článek vyšel v časopise
PLOS One
2020 Číslo 1
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Proč při poslechu některé muziky prostě musíme tančit?
- Je libo čepici místo mozkového implantátu?
- Chůze do schodů pomáhá prodloužit život a vyhnout se srdečním chorobám
- Pomůže v budoucnu s triáží na pohotovostech umělá inteligence?
Nejčtenější v tomto čísle
- Severity of misophonia symptoms is associated with worse cognitive control when exposed to misophonia trigger sounds
- Chemical analysis of snus products from the United States and northern Europe
- Calcium dobesilate reduces VEGF signaling by interfering with heparan sulfate binding site and protects from vascular complications in diabetic mice
- Effect of Lactobacillus acidophilus D2/CSL (CECT 4529) supplementation in drinking water on chicken crop and caeca microbiome
Zvyšte si kvalifikaci online z pohodlí domova
Všechny kurzy