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Modifications of the axon initial segment during the hibernation of the Syrian hamster

  • Gonzalo León-Espinosa
  • Alejandro Antón-Fernández
  • Silvia Tapia-González
  • Javier DeFelipe
  • Alberto Muñoz
Original Article

Abstract

Mammalian hibernation is a natural process in which the brain undergoes profound adaptive changes that appear to protect the brain from extreme hypoxia and hypothermia. In addition to a virtual cessation of neural and metabolic activity, these changes include a decrease in adult neurogenesis; the retraction of neuronal dendritic trees; changes in dendritic spines and synaptic connections; fragmentation of the Golgi apparatus; and the phosphorylation of the microtubule-associated protein tau. Furthermore, alterations of microglial cells also occur in torpor. Importantly, all of these changes are rapidly and fully reversed when the animals arouse from torpor state, with no apparent brain damage occurring. Thus, hibernating animals are excellent natural models to study different aspects of brain plasticity. The axon initial segment (AIS) is critical for the initiation of action potentials in neurons and is an efficient site for the regulation of neural activity. This specialized structure—characterized by the expression of different types of ion channels and adhesion, scaffolding and cytoskeleton proteins—is subjected to morpho-functional plastic changes upon variations in neural activity or in pathological conditions. Here, we used immunocytochemistry and 3D confocal microscopy reconstruction techniques to measure the possible morphological differences in the AIS of neocortical (layers II–III and V) and hippocampal (CA1) neurons during the hibernation of the Syrian hamster. Our results indicate that the general integrity of the AIS is resistant to the ischemia/hypoxia conditions that are characteristic of the torpor phase of hibernation. In addition, the length of the AIS significantly increased in all the regions studied—by about 16–20% in torpor animals compared to controls, suggesting the existence of compensatory mechanisms in response to a decrease in neuronal activity during the torpor phase of hibernation. Furthermore, in double-labeling experiment, we found that the AIS in layer V of torpid animals was longer in neurons expressing phospho-tau than in those not labeled for phospho-tau. This suggests that AIS plastic changes were more marked in phospho-tau accumulating neurons. Overall, the results further emphasize that mammalian hibernation is a good physiological model to study AIS plasticity mechanisms in non-pathological conditions.

Keywords

Hibernation Ankyrin G Cortex Hippocampus Hypothermia 

Notes

Acknowledgements

We thank Soledad Martínez for technical help with the surgical procedures in the middle cerebral artery occlusion experiments and María Albillos and Andrea González for their technical help.

Funding

This work was supported by Grants from the following entities: SAF 2015-66603-P from the Ministerio de Economía y Competitividad; Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED, CB06/05/0066, Spain); and a Grant from the Alzheimer’s Association (ZEN-15-321663).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All experimental procedures were carried out at the animal facility in the San Pablo CEU University of Madrid (SVA-CEU.USP, registration number ES 28022 0000015) and were approved by the institutional Animal Experiment Ethics Committee.

References

  1. Angulo MC, Staiger JF, Rossier J, Audinat E (2003) Distinct local circuits between neocortical pyramidal cells and fast-spiking interneurons in young adult rats. J Neurophysiol 89(2):943–953.  https://doi.org/10.1152/jn.00750.2002 CrossRefPubMedGoogle Scholar
  2. Anton-Fernandez A, Leon-Espinosa G, DeFelipe J, Munoz A (2015) Changes in the Golgi apparatus of neocortical and hippocampal neurons in the hibernating hamster. Front Neuroanat 9:157.  https://doi.org/10.3389/fnana.2015.00157 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Anton-Fernandez A, Aparicio-Torres G, Tapia S, DeFelipe J, Munoz A (2017a) Morphometric alterations of Golgi apparatus in Alzheimer’s disease are related to tau hyperphosphorylation. Neurobiol Dis 97(Pt A):11–23.  https://doi.org/10.1016/j.nbd.2016.10.005 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Anton-Fernandez A, Merchan-Rubira J, Avila J, Hernandez F, DeFelipe J, Munoz A (2017b) Phospho-tau accumulation and structural alterations of the Golgi apparatus of cortical pyramidal neurons in the P301S tauopathy mouse model. J Alzheimers Dis 60(2):651–661.  https://doi.org/10.3233/JAD-170332 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Arellano JI, Munoz A, Ballesteros-Yanez I, Sola RG, DeFelipe J (2004) Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus. Brain 127(Pt 1):45–64.  https://doi.org/10.1093/brain/awh004 CrossRefPubMedGoogle Scholar
  6. Arendt T, Stieler J, Strijkstra AM, Hut RA, Rudiger J, Van der Zee EA, Harkany T, Holzer M, Hartig W (2003) Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 23(18):6972–6981CrossRefGoogle Scholar
  7. Avila J, Lucas JJ, Perez M, Hernandez F (2004) Role of tau protein in both physiological and pathological conditions. Physiol Rev 84(2):361–384.  https://doi.org/10.1152/physrev.00024.2003 CrossRefPubMedGoogle Scholar
  8. Baalman KL, Cotton RJ, Rasband SN, Rasband MN (2013) Blast wave exposure impairs memory and decreases axon initial segment length. J Neurotrauma 30(9):741–751.  https://doi.org/10.1089/neu.2012.2478 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Baranauskas G, David Y, Fleidervish IA (2013) Spatial mismatch between the Na+ flux and spike initiation in axon initial segment. Proc Natl Acad Sci USA 110(10):4051–4056.  https://doi.org/10.1073/pnas.1215125110 CrossRefPubMedGoogle Scholar
  10. Bertrand J, Senechal P, Zummo-Soucy M, Plouffe V, Leclerc N (2010) The formation of tau pathological phospho-epitopes in the axon is prevented by the dephosphorylation of selective sites in primary hippocampal neurons over-expressing human tau. J Neurochem 114(5):1353–1367.  https://doi.org/10.1111/j.1471-4159.2010.06855.x CrossRefPubMedGoogle Scholar
  11. Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101(4):1371–1378CrossRefGoogle Scholar
  12. Bouma HR, Strijkstra AM, Boerema AS, Deelman LE, Epema AH, Hut RA, Kroese FG, Henning RH (2010a) Blood cell dynamics during hibernation in the European Ground Squirrel. Vet Immunol Immunopathol 136(3–4):319–323.  https://doi.org/10.1016/j.vetimm.2010.03.016 CrossRefPubMedGoogle Scholar
  13. Bouma HR, Carey HV, Kroese FG (2010b) Hibernation: the immune system at rest? J Leukoc Biol 88(4):619–624.  https://doi.org/10.1189/jlb.0310174 CrossRefPubMedGoogle Scholar
  14. Buffington SA, Rasband MN (2011) The axon initial segment in nervous system disease and injury. Eur J Neurosci 34(10):1609–1619.  https://doi.org/10.1111/j.1460-9568.2011.07875.x CrossRefPubMedPubMedCentralGoogle Scholar
  15. Bullmann T, Seeger G, Stieler J, Hanics J, Reimann K, Kretzschmann TP, Hilbrich I, Holzer M, Alpar A, Arendt T (2016) Tau phosphorylation-associated spine regression does not impair hippocampal-dependent memory in hibernating golden hamsters. Hippocampus 26(3):301–318.  https://doi.org/10.1002/hipo.22522 CrossRefPubMedGoogle Scholar
  16. Buzadzic B, Spasic M, Saicic ZS, Radojicic R, Petrovic VM, Halliwell B (1990) Antioxidant defenses in the ground squirrel Citellus citellus. 2. The effect of hibernation. Free Radic Biol Med 9(5):407–413CrossRefGoogle Scholar
  17. Buzadzic B, Blagojevic D, Korac B, Saicic ZS, Spasic MB, Petrovic VM (1997) Seasonal variation in the antioxidant defense system of the brain of the ground squirrel (Citellus citellus) and response to low temperature compared with rat. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 117(2):141–149CrossRefGoogle Scholar
  18. Carey HV, Rhoads CA, Aw TY (2003) Hibernation induces glutathione redox imbalance in ground squirrel intestine. J Comp Physiol B 173(4):269–276.  https://doi.org/10.1007/s00360-003-0330-3 CrossRefPubMedGoogle Scholar
  19. Cogut V, Bruintjes JJ, Eggen BJL, van der Zee EA, Henning RH (2017) Brain inflammatory cytokines and microglia morphology changes throughout hibernation phases in Syrian hamster. Brain Behav Immun.  https://doi.org/10.1016/j.bbi.2017.10.009 CrossRefPubMedGoogle Scholar
  20. Cristobo I, Larriba MJ, de los Rios V, Garcia F, Munoz A, Casal JI (2011) Proteomic analysis of 1alpha,25-dihydroxyvitamin D3 action on human colon cancer cells reveals a link to splicing regulation. J Proteomics 75(2):384–397.  https://doi.org/10.1016/j.jprot.2011.08.003 CrossRefPubMedGoogle Scholar
  21. Dave KR, Christian SL, Perez-Pinzon MA, Drew KL (2012) Neuroprotection: lessons from hibernators. Comp Biochem Physiol B Biochem Mol Biol 162(1–3):1–9.  https://doi.org/10.1016/j.cbpb.2012.01.008 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Dietrich WD, Bramlett HM (2010) The evidence for hypothermia as a neuroprotectant in traumatic brain injury. Neurotherapeutics 7(1):43–50.  https://doi.org/10.1016/j.nurt.2009.10.015 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Drew KL, Rice ME, Kuhn TB, Smith MA (2001) Neuroprotective adaptations in hibernation: therapeutic implications for ischemia-reperfusion, traumatic brain injury and neurodegenerative diseases. Free Radic Biol Med 31(5):563–573CrossRefGoogle Scholar
  24. Drew KL, Buck CL, Barnes BM, Christian SL, Rasley BT, Harris MB (2007) Central nervous system regulation of mammalian hibernation: implications for metabolic suppression and ischemia tolerance. J Neurochem 102(6):1713–1726.  https://doi.org/10.1111/j.1471-4159.2007.04675.x CrossRefPubMedPubMedCentralGoogle Scholar
  25. Evans MD, Dumitrescu AS, Kruijssen DL, Taylor SE, Grubb MS (2015) Rapid Modulation of Axon Initial Segment Length Influences Repetitive Spike Firing. Cell Rep 13(6):1233–1245.  https://doi.org/10.1016/j.celrep.2015.09.066 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Frerichs KU, Kennedy C, Sokoloff L, Hallenbeck JM (1994) Local cerebral blood flow during hibernation, a model of natural tolerance to “cerebral ischemia”. J Cereb Blood Flow Metab 14(2):193–205.  https://doi.org/10.1038/jcbfm.1994.26 CrossRefPubMedGoogle Scholar
  27. Frerichs KU, Smith CB, Brenner M, DeGracia DJ, Krause GS, Marrone L, Dever TE, Hallenbeck JM (1998) Suppression of protein synthesis in brain during hibernation involves inhibition of protein initiation and elongation. Proc Natl Acad Sci USA 95(24):14511–14516CrossRefGoogle Scholar
  28. Galiano MR, Jha S, Ho TS, Zhang C, Ogawa Y, Chang KJ, Stankewich MC, Mohler PJ, Rasband MN (2012) A distal axonal cytoskeleton forms an intra-axonal boundary that controls axon initial segment assembly. Cell 149(5):1125–1139.  https://doi.org/10.1016/j.cell.2012.03.039 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Gasser A, Ho TS, Cheng X, Chang KJ, Waxman SG, Rasband MN, Dib-Hajj SD (2012) An ankyrinG-binding motif is necessary and sufficient for targeting Nav1.6 sodium channels to axon initial segments and nodes of Ranvier. J Neurosci 32(21):7232–7243.  https://doi.org/10.1523/JNEUROSCI.5434-11.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Geiser F (2004) Metabolic rate and body temperature reduction during hibernation and daily torpor. Annu Rev Physiol 66:239–274.  https://doi.org/10.1146/annurev.physiol.66.032102.115105 CrossRefPubMedGoogle Scholar
  31. Geiser F (2013) Hibernation. Curr Biol 23(5):R188–R193.  https://doi.org/10.1016/j.cub.2013.01.062 CrossRefPubMedGoogle Scholar
  32. Grubb MS, Burrone J (2010) Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability. Nature 465(7301):1070–1074.  https://doi.org/10.1038/nature09160 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Gutzmann A, Ergul N, Grossmann R, Schultz C, Wahle P, Engelhardt M (2014) A period of structural plasticity at the axon initial segment in developing visual cortex. Front Neuroanat 8:11.  https://doi.org/10.3389/fnana.2014.00011 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hamada MS, Kole MH (2015) Myelin loss and axonal ion channel adaptations associated with gray matter neuronal hyperexcitability. J Neurosci 35(18):7272–7286.  https://doi.org/10.1523/JNEUROSCI.4747-14.2015 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Hartig W, Oklejewicz M, Strijkstra AM, Boerema AS, Stieler J, Arendt T (2005) Phosphorylation of the tau protein sequence 199–205 in the hippocampal CA3 region of Syrian hamsters in adulthood and during aging. Brain Res 1056(1):100–104.  https://doi.org/10.1016/j.brainres.2005.07.017 CrossRefPubMedGoogle Scholar
  36. Hartig W, Stieler J, Boerema AS, Wolf J, Schmidt U, Weissfuss J, Bullmann T, Strijkstra AM, Arendt T (2007) Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons—implications for Alzheimer’s disease. Eur J Neurosci 25(1):69–80.  https://doi.org/10.1111/j.1460-9568.2006.05250.x CrossRefPubMedGoogle Scholar
  37. Harty RC, Kim TH, Thomas EA, Cardamone L, Jones NC, Petrou S, Wimmer VC (2013) Axon initial segment structural plasticity in animal models of genetic and acquired epilepsy. Epilepsy Res 105(3):272–279.  https://doi.org/10.1016/j.eplepsyres.2013.03.004 CrossRefPubMedGoogle Scholar
  38. Hedstrom KL, Ogawa Y, Rasband MN (2008) AnkyrinG is required for maintenance of the axon initial segment and neuronal polarity. J Cell Biol 183(4):635–640.  https://doi.org/10.1083/jcb.200806112 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Hinman JD, Rasband MN, Carmichael ST (2013) Remodeling of the axon initial segment after focal cortical and white matter stroke. Stroke 44(1):182–189.  https://doi.org/10.1161/STROKEAHA.112.668749 CrossRefPubMedGoogle Scholar
  40. Hofflin F, Jack A, Riedel C, Mack-Bucher J, Roos J, Corcelli C, Schultz C, Wahle P, Engelhardt M (2017) Heterogeneity of the axon initial segment in interneurons and pyramidal cells of rodent visual cortex. Front Cell Neurosci 11:332.  https://doi.org/10.3389/fncel.2017.00332 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, Ashe KH, Liao D (2010) Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68(6):1067–1081.  https://doi.org/10.1016/j.neuron.2010.11.030 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Igelmund P (1995) Modulation of synaptic transmission at low temperatures by hibernation-related changes in ionic microenvironment in hippocampal slices of golden hamsters. Cryobiology 32(4):334–343.  https://doi.org/10.1006/cryo.1995.1034 CrossRefPubMedGoogle Scholar
  43. Igelmund P, Heinemann U (1995) Synaptic transmission and paired-pulse behaviour of CA1 pyramidal cells in hippocampal slices from a hibernator at low temperature: importance of ionic environment. Brain Res 689(1):9–20CrossRefGoogle Scholar
  44. Jenkins PM, Kim N, Jones SL, Tseng WC, Svitkina TM, Yin HH, Bennett V (2015) Giant ankyrin-G: a critical innovation in vertebrate evolution of fast and integrated neuronal signaling. Proc Natl Acad Sci USA 112(4):957–964.  https://doi.org/10.1073/pnas.1416544112 CrossRefPubMedGoogle Scholar
  45. Kaphzan H, Buffington SA, Jung JI, Rasband MN, Klann E (2011) Alterations in intrinsic membrane properties and the axon initial segment in a mouse model of Angelman syndrome. J Neurosci 31(48):17637–17648.  https://doi.org/10.1523/JNEUROSCI.4162-11.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Karibe H, Chen SF, Zarow GJ, Gafni J, Graham SH, Chan PH, Weinstein PR (1994) Mild intraischemic hypothermia suppresses consumption of endogenous antioxidants after temporary focal ischemia in rats. Brain Res 649(1–2):12–18CrossRefGoogle Scholar
  47. Katz LM, Young AS, Frank JE, Wang Y, Park K (2004) Regulated hypothermia reduces brain oxidative stress after hypoxic-ischemia. Brain Res 1017(1–2):85–91.  https://doi.org/10.1016/j.brainres.2004.05.020 CrossRefPubMedGoogle Scholar
  48. Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE (2015) The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 10:845.  https://doi.org/10.1038/nprot.2015.053 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Kole MH, Brette R (2018) The electrical significance of axon location diversity. Curr Opin Neurobiol 51:52–59.  https://doi.org/10.1016/j.conb.2018.02.016 CrossRefPubMedGoogle Scholar
  50. Kole MH, Letzkus JJ, Stuart GJ (2007) Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy. Neuron 55(4):633–647.  https://doi.org/10.1016/j.neuron.2007.07.031 CrossRefPubMedGoogle Scholar
  51. Kordeli E, Davis J, Trapp B, Bennett V (1990) An isoform of ankyrin is localized at nodes of Ranvier in myelinated axons of central and peripheral nerves. J Cell Biol 110(4):1341–1352CrossRefGoogle Scholar
  52. Kordeli E, Lambert S, Bennett V (1995) AnkyrinG. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. J Biol Chem 270(5):2352–2359CrossRefGoogle Scholar
  53. Kosik KS, Finch EA (1987) MAP2 and tau segregate into dendritic and axonal domains after the elaboration of morphologically distinct neurites: an immunocytochemical study of cultured rat cerebrum. J Neurosci 7(10):3142–3153CrossRefGoogle Scholar
  54. Krilowicz BL, Edgar DM, Heller HC (1989) Action potential duration increases as body temperature decreases during hibernation. Brain Res 498(1):73–80CrossRefGoogle Scholar
  55. Kuba H, Oichi Y, Ohmori H (2010) Presynaptic activity regulates Na(+) channel distribution at the axon initial segment. Nature 465(7301):1075–1078.  https://doi.org/10.1038/nature09087 CrossRefPubMedGoogle Scholar
  56. Leon-Espinosa G, DeFelipe J, Munoz A (2012) Effects of amyloid-beta plaque proximity on the axon initial segment of pyramidal cells. J Alzheimers Dis 29(4):841–852.  https://doi.org/10.3233/JAD-2012-112036 CrossRefPubMedGoogle Scholar
  57. Leon-Espinosa G, Garcia E, Garcia-Escudero V, Hernandez F, Defelipe J, Avila J (2013) Changes in tau phosphorylation in hibernating rodents. J Neurosci Res 91(7):954–962.  https://doi.org/10.1002/jnr.23220 CrossRefPubMedGoogle Scholar
  58. Leon-Espinosa G, Garcia E, Gomez-Pinedo U, Hernandez F, DeFelipe J, Avila J (2016) Decreased adult neurogenesis in hibernating Syrian hamster. Neuroscience 333:181–192.  https://doi.org/10.1016/j.neuroscience.2016.07.016 CrossRefPubMedGoogle Scholar
  59. Leon-Espinosa G, Regalado-Reyes M, DeFelipe J, Munoz A (2017) Changes in neocortical and hippocampal microglial cells during hibernation. Brain Struct Funct.  https://doi.org/10.1007/s00429-017-1596-7.10.1007/s00429-017-1596-7 CrossRefPubMedGoogle Scholar
  60. Leterrier C (2016) The axon initial segment, 50 years later: a nexus for neuronal organization and function. Curr Top Membr 77:185–233.  https://doi.org/10.1016/bs.ctm.2015.10.005 CrossRefPubMedGoogle Scholar
  61. Li X, Kumar Y, Zempel H, Mandelkow EM, Biernat J, Mandelkow E (2011) Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration. EMBO J 30(23):4825–4837.  https://doi.org/10.1038/emboj.2011.376 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Mandell JW, Banker GA (1996) A spatial gradient of tau protein phosphorylation in nascent axons. J Neurosci 16(18):5727–5740CrossRefGoogle Scholar
  63. Marin MA, Ziburkus J, Jankowsky J, Rasband MN (2016) Amyloid-beta plaques disrupt axon initial segments. Exp Neurol 281:93–98.  https://doi.org/10.1016/j.expneurol.2016.04.018 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Migheli A, Butler M, Brown K, Shelanski ML (1988) Light and electron microscope localization of the microtubule-associated tau protein in rat brain. J Neurosci 8(6):1846–1851CrossRefGoogle Scholar
  65. Molnar Z, Cheung AF (2006) Towards the classification of subpopulations of layer V pyramidal projection neurons. Neurosci Res 55(2):105–115.  https://doi.org/10.1016/j.neures.2006.02.008 CrossRefPubMedGoogle Scholar
  66. Osborne PG, Hashimoto M (2006) Brain antioxidant levels in hamsters during hibernation, arousal and cenothermia. Behav Brain Res 168(2):208–214.  https://doi.org/10.1016/j.bbr.2005.11.007 CrossRefPubMedGoogle Scholar
  67. Piela L, Nemethy G, Scheraga HA (1987) Proline-induced constraints in alpha-helices. Biopolymers 26(9):1587–1600.  https://doi.org/10.1002/bip.360260910 CrossRefPubMedGoogle Scholar
  68. Piironen K, Tiainen M, Mustanoja S, Kaukonen KM, Meretoja A, Tatlisumak T, Kaste M (2014) Mild hypothermia after intravenous thrombolysis in patients with acute stroke: a randomized controlled trial. Stroke 45(2):486–491.  https://doi.org/10.1161/STROKEAHA.113.003180 CrossRefPubMedGoogle Scholar
  69. Popov VI, Bocharova LS (1992) Hibernation-induced structural changes in synaptic contacts between mossy fibres and hippocampal pyramidal neurons. Neuroscience 48(1):53–62CrossRefGoogle Scholar
  70. Popov VI, Bocharova LS, Bragin AG (1992) Repeated changes of dendritic morphology in the hippocampus of ground squirrels in the course of hibernation. Neuroscience 48(1):45–51CrossRefGoogle Scholar
  71. Popov VI, Medvedev NI, Patrushev IV, Ignat’ev DA, Morenkov ED, Stewart MG (2007) Reversible reduction in dendritic spines in CA1 of rat and ground squirrel subjected to hypothermia-normothermia in vivo: A three-dimensional electron microscope study. Neuroscience 149(3):549–560.  https://doi.org/10.1016/j.neuroscience.2007.07.059 CrossRefPubMedGoogle Scholar
  72. Popov VI, Kraev IV, Ignat’ev DA, Stewart MG (2011) Suspension of mitotic activity in dentate gyrus of the hibernating ground squirrel. Neural Plast 2011:867525.  https://doi.org/10.1155/2011/867525 CrossRefPubMedPubMedCentralGoogle Scholar
  73. Rasband MN (2010) The axon initial segment and the maintenance of neuronal polarity. Nat Rev Neurosci 11(8):552–562.  https://doi.org/10.1038/nrn2852 CrossRefPubMedGoogle Scholar
  74. Ross AP, Drew KL (2006) Potential for discovery of neuroprotective factors in serum and tissue from hibernating species. Mini Rev Med Chem 6(8):875–884CrossRefGoogle Scholar
  75. Ruf T, Geiser F (2015) Daily torpor and hibernation in birds and mammals. Biol Rev Camb Philos Soc 90(3):891–926.  https://doi.org/10.1111/brv.12137 CrossRefPubMedGoogle Scholar
  76. Schafer DP, Jha S, Liu F, Akella T, McCullough LD, Rasband MN (2009) Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury. J Neurosci 29(42):13242–13254.  https://doi.org/10.1523/JNEUROSCI.3376-09.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  77. Sorensen SA, Bernard A, Menon V, Royall JJ, Glattfelder KJ, Hirokawa K, Mortrud M, Miller JA, Zeng H, Hohmann JG, Jones AR, Lein ES (2013) Correlated Gene Expression and Target Specificity Demonstrate Excitatory Projection Neuron Diversity. Cereb Cortex.  https://doi.org/10.1093/cercor/bht243 CrossRefPubMedGoogle Scholar
  78. South FE (1972) Hibernation and hypothermia, perspectives and challenges. Symposium held at Snow-mass-at-Aspen, Colorado, 1971. Elsevier Pub. Co., Amsterdam, New YorkGoogle Scholar
  79. Srinivasan Y, Elmer L, Davis J, Bennett V, Angelides K (1988) Ankyrin and spectrin associate with voltage-dependent sodium channels in brain. Nature 333(6169):177–180.  https://doi.org/10.1038/333177a0 CrossRefPubMedGoogle Scholar
  80. Srinivasan Y, Lewallen M, Angelides KJ (1992) Mapping the binding site on ankyrin for the voltage-dependent sodium channel from brain. J Biol Chem 267(11):7483–7489PubMedGoogle Scholar
  81. Stieler JT, Bullmann T, Kohl F, Toien O, Bruckner MK, Hartig W, Barnes BM, Arendt T (2011) The physiological link between metabolic rate depression and tau phosphorylation in mammalian hibernation. PLoS One 6(1):e14530.  https://doi.org/10.1371/journal.pone.0014530 CrossRefPubMedPubMedCentralGoogle Scholar
  82. Stoler O, Fleidervish IA (2016) Functional implications of axon initial segment cytoskeletal disruption in stroke. Acta Pharmacol Sin 37(1):75–81.  https://doi.org/10.1038/aps.2015.107 CrossRefPubMedGoogle Scholar
  83. Strumwasser F (1959a) Factors in the pattern, timing and predictability of hibernation in the squirrel, Citellus beecheyi. Am J Physiol 196(1):8–14PubMedGoogle Scholar
  84. Strumwasser F (1959b) Regulatory mechanisms, brain activity and behavior during deep hibernation in the squirrel, Citellus beecheyi. Am J Physiol 196(1):23–30PubMedGoogle Scholar
  85. Strumwasser F (1959c) Thermoregulatory, brain and behavioral mechanisms during entrance into hibernation in the squirrel, Citellus beecheyi. Am J Physiol 196(1):15–22PubMedGoogle Scholar
  86. Su B, Wang X, Drew KL, Perry G, Smith MA, Zhu X (2008) Physiological regulation of tau phosphorylation during hibernation. J Neurochem 105(6):2098–2108.  https://doi.org/10.1111/j.1471-4159.2008.05294.x CrossRefPubMedPubMedCentralGoogle Scholar
  87. Thies E, Mandelkow EM (2007) Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. J Neurosci 27(11):2896–2907.  https://doi.org/10.1523/JNEUROSCI.4674-06.2007 CrossRefPubMedGoogle Scholar
  88. Tsiola A, Hamzei-Sichani F, Peterlin Z, Yuste R (2003) Quantitative morphologic classification of layer 5 neurons from mouse primary visual cortex. J Comp Neurol 461(4):415–428.  https://doi.org/10.1002/cne.10628 CrossRefPubMedGoogle Scholar
  89. Vascak M, Sun J, Baer M, Jacobs KM, Povlishock JT (2017) Mild traumatic brain injury evokes pyramidal neuron axon initial Segment plasticity and diffuse presynaptic inhibitory terminal loss. Front Cell Neurosci 11:157.  https://doi.org/10.3389/fncel.2017.00157 CrossRefPubMedPubMedCentralGoogle Scholar
  90. von der Ohe CG, Darian-Smith C, Garner CC, Heller HC (2006) Ubiquitous and temperature-dependent neural plasticity in hibernators. J Neurosci 26(41):10590–10598.  https://doi.org/10.1523/JNEUROSCI.2874-06.2006 CrossRefPubMedGoogle Scholar
  91. von der Ohe CG, Garner CC, Darian-Smith C, Heller HC (2007) Synaptic protein dynamics in hibernation. J Neurosci 27(1):84–92.  https://doi.org/10.1523/JNEUROSCI.4385-06.2007 CrossRefPubMedGoogle Scholar
  92. Vucetic M, Stancic A, Otasevic V, Jankovic A, Korac A, Markelic M, Velickovic K, Golic I, Buzadzic B, Storey KB, Korac B (2013) The impact of cold acclimation and hibernation on antioxidant defenses in the ground squirrel (Spermophilus citellus): an update. Free Radic Biol Med 65:916–924.  https://doi.org/10.1016/j.freeradbiomed.2013.08.188 CrossRefPubMedGoogle Scholar
  93. Walker JM, Glotzbach SF, Berger RJ, Heller HC (1977) Sleep and hibernation in ground squirrels (Citellus spp.): electrophysiological observations. Am J Physiol 233(5):R213–R221PubMedGoogle Scholar
  94. Wefelmeyer W, Cattaert D, Burrone J (2015) Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output. Proc Natl Acad Sci USA 112(31):9757–9762.  https://doi.org/10.1073/pnas.1502902112 CrossRefPubMedGoogle Scholar
  95. Wefelmeyer W, Puhl CJ, Burrone J (2016) Homeostatic plasticity of subcellular neuronal structures: from inputs to outputs. Trends Neurosci 39(10):656–667.  https://doi.org/10.1016/j.tins.2016.08.004 CrossRefPubMedPubMedCentralGoogle Scholar
  96. Wu D, Shi J, Elmadhoun O, Duan Y, An H, Zhang J, He X, Meng R, Liu X, Ji X, Ding Y (2017) Dihydrocapsaicin (DHC) enhances the hypothermia-induced neuroprotection following ischemic stroke via PI3K/Akt regulation in rat. Brain Res 1671:18–25.  https://doi.org/10.1016/j.brainres.2017.06.029 CrossRefPubMedGoogle Scholar
  97. Yamada R, Kuba H (2016) Structural and functional plasticity at the axon initial segment. Front Cell Neurosci 10:250.  https://doi.org/10.3389/fncel.2016.00250 CrossRefPubMedPubMedCentralGoogle Scholar
  98. Yenari MA, Han HS (2012) Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 13(4):267–278.  https://doi.org/10.1038/nrn3174 CrossRefPubMedGoogle Scholar
  99. Yenari MA, Hemmen TM (2010) Therapeutic hypothermia for brain ischemia: where have we come and where do we go? Stroke 41 (10 Suppl):S72–S74.  https://doi.org/10.1161/STROKEAHA.110.595371 CrossRefGoogle Scholar
  100. Yin Q, Ge H, Liao CC, Liu D, Zhang S, Pan YH (2016) Antioxidant defenses in the brains of bats during hibernation. PLoS One 11(3):e0152135.  https://doi.org/10.1371/journal.pone.0152135 CrossRefPubMedPubMedCentralGoogle Scholar
  101. Yun RH, Anderson A, Hermans J (1991) Proline in alpha-helix: stability and conformation studied by dynamics simulation. Proteins 10(3):219–228.  https://doi.org/10.1002/prot.340100306 CrossRefPubMedGoogle Scholar
  102. Zempel H, Dennissen FJA, Kumar Y, Luedtke J, Biernat J, Mandelkow EM, Mandelkow E (2017) Axodendritic sorting and pathological missorting of Tau are isoform-specific and determined by axon initial segment architecture. J Biol Chem 292(29):12192–12207.  https://doi.org/10.1074/jbc.M117.784702 CrossRefPubMedPubMedCentralGoogle Scholar
  103. Zhou F, Zhu X, Castellani RJ, Stimmelmayr R, Perry G, Smith MA, Drew KL (2001) Hibernation, a model of neuroprotection. Am J Pathol 158(6):2145–2151.  https://doi.org/10.1016/S0002-9440(10)64686-X CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Instituto Cajal, CSICMadridSpain
  2. 2.Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica (CTB)Universidad Politécnica de MadridMadridSpain
  3. 3.CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades NeurodegenerativasMadridSpain
  4. 4.Departamento de Biología CelularUniversidad ComplutenseMadridSpain
  5. 5.Facultad de FarmaciaUniversidad San Pablo CEUMadridSpain

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