Skip to main content

Advertisement

SpringerLink
Log in

Moderate Treadmill Exercise Protects Synaptic Plasticity of the Dentate Gyrus and Related Signaling Cascade in a Rat Model of Alzheimer’s Disease

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

A Correction to this article was published on 05 October 2017

This article has been updated

Abstract

The dentate gyrus (DG) of the hippocampus is known to be more resistant to the effects of various external factors than other hippocampal areas. This study investigated the neuroprotective effects of moderate treadmill exercise on early-phase long-term potentiation (E-LTP) and its molecular signaling pathways in the DG of amyloid β rat model of sporadic Alzheimer’s disease (AD). Animals were preconditioned to run on treadmill for 4 weeks and concurrently received ICV infusion of Aβ1–42 peptides (250 pmol/day) during the third and fourth weeks of exercise training. We utilized in vivo electrophysiological recordings to assess the effect of exercise and/or AD pathology on basal synaptic transmission and E-LTP magnitude of the perforant pathway synapses in urethane-anesthetized rats. Immunoblotting analysis was used to quantify changes in the levels of learning and memory-related key signaling molecules. The AD-impaired basal synaptic transmission and suppression of E-LTP in the DG were prevented by prior moderate treadmill exercise. In addition, exercise normalized the basal levels of memory and E-LTP-related signaling molecules including Ca2+/calmodulin-dependent protein kinase II (CaMKII), calcineurin (PP2B), and brain-derived neurotrophic factor (BDNF). Exercise also prevented the reduction of phosphorylated CaMKII and aberrant increase of PP2B seen after E-LTP induction in amyloid-infused rats. Our data suggests that by restoring the balance of kinase–phosphatase, 4 weeks of moderate treadmill exercise prevents DG synaptic deficits and deleterious alterations in signaling pathways associated with AD.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Change history

  • 05 October 2017

    A correction to this article has been published.

References

  1. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 3:186–191

    Article  PubMed  Google Scholar 

  2. Olton DS, Walker JA, Gage FH (1978) Hippocampal connections and spatial discrimination. Brain Res 139:295–308

    Article  CAS  PubMed  Google Scholar 

  3. Kesner RP (2013) An analysis of the dentate gyrus function. Behav Brain Res 254:1–7

    Article  PubMed  Google Scholar 

  4. Kesner RP (2013) A process analysis of the CA3 subregion of the hippocampus. Front Cell Neurosci 7:78

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vivar C, van Praag H (2013) Functional circuits of new neurons in the dentate gyrus. Front Neural Circuits 7:15

    Article  PubMed  PubMed Central  Google Scholar 

  6. Moser MB, Moser EI (1998) Functional differentiation in the hippocampus. Hippocampus 8:608–619

    Article  CAS  PubMed  Google Scholar 

  7. Potvin O, Allen K, Thibaudeau G, Dore FY, Goulet S (2006) Performance on spatial working memory tasks after dorsal or ventral hippocampal lesions and adjacent damage to the subiculum. Behav Neurosci 120:413–422

    Article  PubMed  Google Scholar 

  8. Bast T (2007) Toward an integrative perspective on hippocampal function: from the rapid encoding of experience to adaptive behavior. Rev Neurosci 18:253–281

    Article  PubMed  Google Scholar 

  9. Iascone DM, Padidam S, Pyfer MS, Zhang X, Zhao L, Chin J (2013) Impairments in neurogenesis are not tightly linked to depressive behavior in a transgenic mouse model of Alzheimer’s disease. PLoS One 8:e79651

    Article  PubMed  PubMed Central  Google Scholar 

  10. Rodriguez JJ, Noristani HN, Hilditch T, Olabarria M, Yeh CY, Witton J, Verkhratsky A (2013) Increased densities of resting and activated microglia in the dentate gyrus follow senile plaque formation in the CA1 subfield of the hippocampus in the triple transgenic model of Alzheimer’s disease. Neurosci Lett 552:129–134

    Article  CAS  PubMed  Google Scholar 

  11. Zagaar M, Alhaider I, Dao A, Levine A, Alkarawi A, Alzubaidy M, Alkadhi K (2012) The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiol Dis 45:1153–1162

    Article  CAS  PubMed  Google Scholar 

  12. Zagaar M, Dao A, Levine A, Alhaider I, Alkadhi K (2013) Regular exercise prevents sleep deprivation associated impairment of long-term memory and synaptic plasticity in the CA1 area of the hippocampus. Sleep 36:751–761

    Article  PubMed  PubMed Central  Google Scholar 

  13. Gerecke KM, Kolobova A, Allen S, Fawer JL (2013) Exercise protects against chronic restraint stress-induced oxidative stress in the cortex and hippocampus. Brain Res 1509:66–78

    Article  CAS  PubMed  Google Scholar 

  14. Hopkins ME, Nitecki R, Bucci DJ (2011) Physical exercise during adolescence versus adulthood: differential effects on object recognition memory and brain-derived neurotrophic factor levels. Neuroscience 194:84–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hashemi Nosrat Abadi T, Vaghef L, Babri S, Mahmood-Alilo M, Beirami M (2013) Effects of different exercise protocols on ethanol-induced spatial memory impairment in adult male rats. Alcohol 47:309–316

    Article  CAS  PubMed  Google Scholar 

  16. Hosseini N, Alaei H, Reisi P, Radahmadi M (2013) The effect of treadmill running on passive avoidance learning in animal model of Alzheimer disease. Int J Prev Med 4:187–192

    PubMed  PubMed Central  Google Scholar 

  17. Yu Q, Li X, Wang J, Li Y (2013) Effect of exercise training on long-term potentiation and NMDA receptor channels in rats with cerebral infarction. Exp Ther Med 6:1431–1436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nadel J, Huang T, Xia Z, Burlin T, Zametkin A, Smith CB (2013) Voluntary exercise regionally augments rates of cerebral protein synthesis. Brain Res 1537:125–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bechara RG, Kelly AM (2013) Exercise improves object recognition memory and induces BDNF expression and cell proliferation in cognitively enriched rats. Behav Brain Res 245:96–100

    Article  CAS  PubMed  Google Scholar 

  20. Hosseinzadeh S, Roshan VD, Mahjoub S (2013) Continuous exercise training and curcumin attenuate changes in brain-derived neurotrophic factor and oxidative stress induced by lead acetate in the hippocampus of male rats. Pharm Biol 51:240–245

    Article  CAS  PubMed  Google Scholar 

  21. Vollert C, Zagaar M, Hovatta I, Taneja M, Vu A, Dao A, Levine A, Alkadhi K, Salim S (2011) Exercise prevents sleep deprivation-associated anxiety-like behavior in rats: potential role of oxidative stress mechanisms. Behav Brain Res 224:233–240

    Article  CAS  PubMed  Google Scholar 

  22. Dao AT, Zagaar MA, Levine AT, Salim S, Eriksen JL, Alkadhi KA (2013) Treadmill exercise prevents learning and memory impairment in Alzheimer’s disease-like pathology. Curr Alzheimer Res 10:507–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dao AT, Zagaar MA, Salim S, Eriksen JL, Alkadhi KA (2014) Regular exercise prevents non-cognitive disturbances in a rat model of Alzheimer’s disease. Int J Neuropsychopharmacol 17:593–602

    Article  CAS  PubMed  Google Scholar 

  24. Srivareerat M, Tran TT, Alzoubi KH, Alkadhi KA (2009) Chronic psychosocial stress exacerbates impairment of cognition and long-term potentiation in beta-amyloid rat model of Alzheimer’s disease. Biol Psychiatry 65:918–926

    Article  CAS  PubMed  Google Scholar 

  25. Tran TT, Srivareerat M, Alkadhi KA (2010) Chronic psychosocial stress triggers cognitive impairment in a novel at-risk model of Alzheimer’s disease. Neurobiol Dis 37:756–763

    Article  CAS  PubMed  Google Scholar 

  26. Maggi CA, Meli A (1986) Suitability of urethane anesthesia for physiopharmacological investigations in various systems. Part 1: general considerations. Experientia 42:109–114

    Article  CAS  PubMed  Google Scholar 

  27. Aleisa AM, Alzoubi KH, Alkadhi KA (2006) Chronic but not acute nicotine treatment reverses stress-induced impairment of LTP in anesthetized rats. Brain Res 1097:78–84

    Article  CAS  PubMed  Google Scholar 

  28. Papatheodoropoulos C, Kostopoulos G (2000) Decreased ability of rat temporal hippocampal CA1 region to produce long-term potentiation. Neurosci Lett 279:177–180

    Article  CAS  PubMed  Google Scholar 

  29. Alzoubi KH, Aleisa AM, Alkadhi KA (2010) In vivo expression of ganglionic long-term potentiation in superior cervical ganglia from hypertensive aged rats. Neurobiol Aging 31:805–812

    Article  CAS  PubMed  Google Scholar 

  30. Alzoubi KH, Alhaider IA, Tran TT, Mosely A, Alkadhi KK (2011) Impaired neural transmission and synaptic plasticity in superior cervical ganglia from beta-amyloid rat model of Alzheimer’s disease. Curr Alzheimer Res 8:377–384

    Article  CAS  PubMed  Google Scholar 

  31. Babri S, Amani M, Mohaddes G, Alihemmati A, Ebrahimi H (2012) Effect of aggregated β-amyloid (1-42) on synaptic plasticity of hippocampal dentate gyrus granule cells in vivo. Bioimpacts 2:189–194

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang Y, Zhang P, Shen X, Tian S, Wu Y, Zhu Y, Jia J, Wu J, Hu Y (2013) Early exercise protects the blood-brain barrier from ischemic brain injury via the regulation of MMP-9 and occludin in rats. Int J Mol Sci 14:11096–11112

    Article  PubMed  PubMed Central  Google Scholar 

  33. Dominguez-del-Toro E, Rodriguez-Moreno A, Porras-Garcia E, Sanchez-Campusano R, Blanchard V, Laville M, Bohme GA, Benavides J, Delgado-Garcia JM (2004) An in vitro and in vivo study of early deficits in associative learning in transgenic mice that over-express a mutant form of human APP associated with Alzheimer’s disease. Eur J Neurosci 20:1945–1952

    Article  PubMed  Google Scholar 

  34. Auffret A, Gautheron V, Mattson MP, Mariani J, Rovira C (2010) Progressive age-related impairment of the late long-term potentiation in Alzheimer’s disease presenilin-1 mutant knock-in mice. J Alzheimers Dis 19:1021–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chong SA, Benilova I, Shaban H, De Strooper B, Devijver H, Moechars D, Eberle W, Bartic C, Van Leuven F, Callewaert G (2011) Synaptic dysfunction in hippocampus of transgenic mouse models of Alzheimer’s disease: a multi-electrode array study. Neurobiol Dis 44:284–291

    Article  CAS  PubMed  Google Scholar 

  36. Ye H, Jalini S, Mylvaganam S, Carlen P (2010) Activation of large-conductance Ca(2+)-activated K(+) channels depresses basal synaptic transmission in the hippocampal CA1 area in APP (swe/ind) TgCRND8 mice. Neurobiol Aging 31:591–604

    Article  CAS  PubMed  Google Scholar 

  37. Hsu JC, Zhang Y, Takagi N, Gurd JW, Wallace MC, Zhang L, Eubanks JH (1998) Decreased expression and functionality of NMDA receptor complexes persist in the CA1, but not in the dentate gyrus after transient cerebral ischemia. J Cerebr Blood F Met 18:768–775

    Article  CAS  Google Scholar 

  38. Yao H, Huang YH, Liu ZW, Wan Q, Ding AS, Zhao B, Fan M, Wang FZ (1998) The different responses to anoxia in cultured CA1 and DG neurons from newborn rats. Sheng Li Xue Bao 50:61–66

    CAS  PubMed  Google Scholar 

  39. Xiong ZQ, Stringer JL (2000) Extracellular pH responses in CA1 and the dentate gyrus during electrical stimulation, seizure discharges, and spreading depression. J Neurophysiol 83:3519–3524

    CAS  PubMed  Google Scholar 

  40. Song D, Xie X, Wang Z, Berger TW (2001) Differential effect of TEA on long-term synaptic modification in hippocampal CA1 and dentate gyrus in vitro. Neurobiol Learn Mem 76:375–387

    Article  CAS  PubMed  Google Scholar 

  41. Abrahám H, Veszprémi B, Kravják A, Kovács K, Gömöri E, Seress L (2009) Ontogeny of calbindin immunoreactivity in the human hippocampal formation with a special emphasis on granule cells of the dentate gyrus. Int J Dev Neurosci 27(2):115–127

    Article  PubMed  Google Scholar 

  42. Abrahám H, Richter Z, Gyimesi C, Horváth Z, Janszky J, Dóczi T, Seress L (2011) Degree and pattern of calbindin immunoreactivity in granule cells of the dentate gyrus differ in mesial temporal sclerosis, cortical malformation- and tumor-related epilepsies. Brain Res 1399:66–78

    Article  PubMed  Google Scholar 

  43. Westerink RH, Beekwilder JP, Wadman WJ (2012) Differential alterations of synaptic plasticity in dentate gyrus and CA1 hippocampal area of Calbindin-D28K knockout mice. Brain Res 1450:1–10

    Article  CAS  PubMed  Google Scholar 

  44. Frantz GD, Tobin AJ (1994) Cellular distribution of calbindin D28K mRNAs in the adult mouse brain. J Neurosci Res 37(3):287–302

    Article  CAS  PubMed  Google Scholar 

  45. Muller A, Kukley M, Stausberg P, Beck H, Muller W, Dietrich D (2005) Endogenous Ca2+ buffer concentration and Ca2+ microdomains in hippocampal neurons. J Neurosci 25:558–565

    Article  PubMed  Google Scholar 

  46. Schwaller B (2010) Cytosolic Ca2+ buffers. Cold Spring Harb Perspect Biol 2:a004051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Scharfman HE, Schwartzkroin PA (1989) Protection of dentate hilar cells from prolonged stimulation by intracellular calcium chelation. Science 246(4927):257–260

    Article  CAS  PubMed  Google Scholar 

  48. Kelly PT, McGuinness TL, Greengard P (1984) Evidence that the major postsynaptic density protein is a component of a Ca2+/calmodulin-dependent protein kinase. Proc Natl Acad Sci U S A 81:945–949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Takamatsu Y, Kishimoto Y, Ohsako S (2003) Immunohistochemical study of Ca2+/calmodulin-dependent protein kinase II in the Drosophila brain using a specific monoclonal antibody. Brain Res 974:99–116

    Article  CAS  PubMed  Google Scholar 

  50. Lisman JE, Zhabotinsky AM (2001) A model of synaptic memory: a CaMKII/PP1 switch that potentiates transmission by organizing an AMPA receptor anchoring assembly. Neuron 31:191–201

    Article  CAS  PubMed  Google Scholar 

  51. Shonesy BC, Jalan-Sakrikar N, Cavener VS, Colbran RJ (2014) CaMKII: a molecular substrate for synaptic plasticity and memory. Prog Mol Biol Transl Sci 122:61–87

    Article  CAS  PubMed  Google Scholar 

  52. Ohno M, Frankland PW, Silva AJ (2002) A pharmacogenetic inducible approach to the study of NMDA/alphaCaMKII signaling in synaptic plasticity. Curr Biol 12:654–656

    Article  CAS  PubMed  Google Scholar 

  53. Yamagata Y, Kobayashi S, Umeda T, Inoue A, Sakagami H, Fukaya M, Watanabe M, Hatanaka N, Totsuka M, Yagi T, Obata K, Imoto K, Yanagawa Y, Manabe T, Okabe S (2009) Kinase-dead knock-in mouse reveals an essential role of kinase activity of Ca2+/calmodulin-dependent protein kinase IIalpha in dendritic spine enlargement, long-term potentiation, and learning. J Neurosci 29:7607–7618

    Article  CAS  PubMed  Google Scholar 

  54. Knobloch M, Farinelli M, Konietzko U, Nitsch RM, Mansuy IM (2007) Abeta oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms. J Neurosci 27:7648–7653

    Article  CAS  PubMed  Google Scholar 

  55. Cavallucci V, Berretta N, Nobili A, Nistico R, Mercuri NB, D’Amelio M (2013) Calcineurin inhibition rescues early synaptic plasticity deficits in a mouse model of Alzheimer’s disease. Neruomol Med 15:541–548

    Article  CAS  Google Scholar 

  56. Czurko A, Hirase H, Csicsvari J, Buzsáki G (1999) Sustained activation of hippocampal pyramidal cells by ‘space clamping’ in a running wheel. Eur J Neurosci 11(1):344–352

    Article  CAS  PubMed  Google Scholar 

  57. Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP (2007) Role of myokines in exercise and metabolism. J Appl Physiol 103:1093–1098

    Article  CAS  PubMed  Google Scholar 

  58. Pedersen BK (2011) Muscles and their myokines. J Exp Biol 214:337–346

    Article  CAS  PubMed  Google Scholar 

  59. Vaynman S, Ying Z, Wu A, Gomez-Pinilla F (2006) Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity. Neuroscience 139(4):1221–1234

    Article  CAS  PubMed  Google Scholar 

  60. Vaynman S, Ying Z, Gomez-Pinilla F (2003) Interplay between brain derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience 122(3):647–657

    Article  CAS  PubMed  Google Scholar 

  61. Zha D, Watson JB, Xie CW (2004) Amyloid beta prevents activation of calcium/calmodulin-dependent protein kinase II and AMPA receptor phosphorylation during hippocampal long-term potentiation. J Neurophysiol 92(5):2853–2858

    Article  Google Scholar 

  62. Pedersen BK, Pedersen M, Krabbe KS, Bruunsgaard H, Matthews VB, Febbraio MA (2009) Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals. Exp Physiol 94:1153–1160

    Article  CAS  PubMed  Google Scholar 

  63. Leal G, Comprido D, Duarte CB (2014) BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology 76(Pt C):639–656

    Article  CAS  PubMed  Google Scholar 

  64. Lommatzsch M, Braun A, Mannsfeldt A, Botchkarev VA, Botchkareva NV, Paus R, Fischer A, Lewin GR, Renz H (1999) Abundant production of brain-derived neurotrophic factor by adult visceral epithelia. Implications for paracrine and target-derived neurotrophic functions. Am J Pathol 155:1183–1193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Poduslo JF, Curran GL (1996) Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res 36:280–286

    Article  CAS  PubMed  Google Scholar 

  66. Matthews VB, Aström MB, Chan MH, Bruce CR, Krabbe KS et al (2009) Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 52:1409–1418

    Article  CAS  PubMed  Google Scholar 

  67. Alkadhi K (2011) Exercised muscles and the brain. Clin Exp Pharmacol 2:e116. doi:10.4172/21611459.1000e116

    Google Scholar 

  68. Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8:45765

    Article  Google Scholar 

Download references

Acknowledgments

This study was funded by grants (SGP) from the University of Houston.

Conflict of Interest

The authors disclose no conflict of biomedical or financial interest.

Author information

Authors and Affiliations

  1. Department of PPS, College of Pharmacy, University of Houston, Houston, TX, 77204-5037, USA

    An T. Dao, Munder A. Zagaar & Karim A. Alkadhi

Authors
  1. An T. Dao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Munder A. Zagaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karim A. Alkadhi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karim A. Alkadhi.

Additional information

A correction to this article is available online at https://doi.org/10.1007/s12035-017-0788-8.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dao, A.T., Zagaar, M.A. & Alkadhi, K.A. Moderate Treadmill Exercise Protects Synaptic Plasticity of the Dentate Gyrus and Related Signaling Cascade in a Rat Model of Alzheimer’s Disease. Mol Neurobiol 52, 1067–1076 (2015). https://doi.org/10.1007/s12035-014-8916-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8916-1

Keywords

Search

Navigation