Advertisement

Expression of a Constitutively Active Human Insulin Receptor in Hippocampal Neurons Does Not Alter VGCC Currents

  • H. N. Frazier
  • K. L. Anderson
  • S. Maimaiti
  • A. O. Ghoweri
  • S. D. Kraner
  • G. J. Popa
  • K. K. Hampton
  • M. D. Mendenhall
  • C. M. Norris
  • R. J. Craven
  • O. Thibault
Original Paper
  • 94 Downloads

Abstract

Memory and cognitive decline are the product of numerous physiological changes within the aging brain. Multiple theories have focused on the oxidative, calcium, cholinergic, vascular, and inflammation hypotheses of brain aging, with recent evidence suggesting that reductions in insulin signaling may also contribute. Specifically, a reduction in insulin receptor density and mRNA levels has been implicated, however, overcoming these changes remains a challenge. While increasing insulin receptor occupation has been successful in offsetting cognitive decline, alternative molecular approaches should be considered as they could bypass the need for brain insulin delivery. Moreover, this approach may be favorable to test the impact of continued insulin receptor signaling on neuronal function. Here we used hippocampal cultures infected with lentivirus with or without IRβ, a constitutively active, truncated form of the human insulin receptor, to characterize the impact continued insulin receptor signaling on voltage-gated calcium channels. Infected cultures were harvested between DIV 13 and 17 (48 h after infection) for Western blot analysis on pAKT and AKT. These results were complemented with whole-cell patch-clamp recordings of individual pyramidal neurons starting 96 h post-infection. Results indicate that while a significant increase in neuronal pAKT/AKT ratio was seen at the time point tested, effects on voltage-gated calcium channels were not detected. These results suggest that there is a significant difference between constitutively active insulin receptors and the actions of insulin on an intact receptor, highlighting potential alternate mechanisms of neuronal insulin resistance and mode of activation.

Keywords

Calcium Electrophysiology Insulin resistance Memory 

Abbreviations

IR

Insulin receptor

AHP

Afterhyperpolarization

VGCC

Voltage-gated Ca2+ channel

SEM

Standard error of the mean

TTX

Tetrodotoxin

CICR

Calcium-induced calcium-release

DIV

Days in vitro

Notes

Acknowledgements

We acknowledge the National Institute of Health for sources of funding for these experiments: Thibault, O. (R01AG033649); Frazier, H. and Hampton, K.K. (T32DK007778). The authors acknowledge the use of facilities in the University of Kentucky Center for Molecular Medicine Genetic Technologies Core. This core is supported in part by National Institute of Health Grant Number P30GM110787.

References

  1. 1.
    Lin JW, Ju W, Foster K, Lee SH, Ahmadian G, Wyszynski M, Wang YT, Sheng M (2000) Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization. Nat Neurosci 3(12):1282–1290.  https://doi.org/10.1038/81814 CrossRefPubMedGoogle Scholar
  2. 2.
    Man HY, Lin JW, Ju WH, Ahmadian G, Liu L, Becker LE, Sheng M, Wang YT (2000) Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron 25(3):649–662CrossRefPubMedGoogle Scholar
  3. 3.
    Skeberdis VA, Lan J, Opitz T, Zheng X, Bennett MV, Zukin RS (2001) mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C. Neuropharmacology 40(7):856–865CrossRefPubMedGoogle Scholar
  4. 4.
    Vetiska SM, Ahmadian G, Ju W, Liu L, Wymann MP, Wang YT (2007) GABAA receptor-associated phosphoinositide 3-kinase is required for insulin-induced recruitment of postsynaptic GABAA receptors. Neuropharmacology 52(1):146–155.  https://doi.org/10.1016/j.neuropharm.2006.06.023 CrossRefPubMedGoogle Scholar
  5. 5.
    Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT (1997) Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388(6643):686–690.  https://doi.org/10.1038/41792 CrossRefPubMedGoogle Scholar
  6. 6.
    Akintola AA, van Opstal AM, Westendorp RG, Postmus I, van der Grond J, van Heemst D (2017) Effect of intranasally administered insulin on cerebral blood flow and perfusion: a randomized experiment in young and older adults. Aging (Albany NY) 9(3):790–802.  https://doi.org/10.18632/aging.101192 Google Scholar
  7. 7.
    Anderson KL, Frazier HN, Maimaiti S, Bakshi VV, Majeed ZR, Brewer LD, Porter NM, Lin AL, Thibault O (2016) Impact of single or repeated dose intranasal zinc-free insulin in young and aged F344 rats on cognition, signaling, and brain metabolism. J Gerontol A.  https://doi.org/10.1093/gerona/glw065 Google Scholar
  8. 8.
    Novak V, Milberg W, Hao Y, Munshi M, Novak P, Galica A, Manor B, Roberson P, Craft S, Abduljalil A (2014) Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 37(3):751–759.  https://doi.org/10.2337/dc13-1672 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Rajasekar N, Nath C, Hanif K, Shukla R (2017) Intranasal insulin improves cerebral blood flow, Nrf-2 expression and BDNF in STZ (ICV)-induced memory impaired rats. Life Sci 173:1–10.  https://doi.org/10.1016/j.lfs.2016.09.020 CrossRefPubMedGoogle Scholar
  10. 10.
    Schilling TM, Ferreira de Sa DS, Westerhausen R, Strelzyk F, Larra MF, Hallschmid M, Savaskan E, Oitzl MS, Busch HP, Naumann E, Schachinger H (2014) Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation. Hum Brain Mapp 35(5):1944–1956.  https://doi.org/10.1002/hbm.22304 CrossRefPubMedGoogle Scholar
  11. 11.
    Grillo CA, Piroli GG, Hendry RM, Reagan LP (2009) Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent. Brain Res 1296:35–45.  https://doi.org/10.1016/j.brainres.2009.08.005 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    McNay EC, Sandusky LA, Pearson-Leary J (2013) Hippocampal insulin microinjection and in vivo microdialysis during spatial memory testing. J Vis Exp (71):e4451.  https://doi.org/10.3791/4451 Google Scholar
  13. 13.
    Chik CL, Li B, Karpinski E, Ho AK (1997) Insulin and insulin-like growth factor-I inhibit the L-type calcium channel current in rat pinealocytes. Endocrinology 138(5):2033–2042.  https://doi.org/10.1210/endo.138.5.5129 CrossRefPubMedGoogle Scholar
  14. 14.
    Maimaiti S, Frazier HN, Anderson KL, Ghoweri AO, Brewer LD, Porter NM, Thibault O (2017) Novel calcium-related targets of insulin in hippocampal neurons. Neuroscience 364:130–142.  https://doi.org/10.1016/j.neuroscience.2017.09.019 CrossRefPubMedGoogle Scholar
  15. 15.
    Stella SL Jr, Bryson EJ, Thoreson WB (2001) Insulin inhibits voltage-dependent calcium influx into rod photoreceptors. Neuroreport 12(5):947–951CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Adzovic L, Lynn AE, D’Angelo HM, Crockett AM, Kaercher RM, Royer SE, Hopp SC, Wenk GL (2015) Insulin improves memory and reduces chronic neuroinflammation in the hippocampus of young but not aged brains. J Neuroinflamm 12:63.  https://doi.org/10.1186/s12974-015-0282-z CrossRefGoogle Scholar
  17. 17.
    Frolich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Turk A, Hoyer S, Zochling R, Boissl KW, Jellinger K, Riederer P (1998) Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm (Vienna) 105(4–5):423–438.  https://doi.org/10.1007/s007020050068 CrossRefGoogle Scholar
  18. 18.
    Zaia A, Piantanelli L (1996) Alterations of brain insulin receptor characteristics in aging mice. Arch Gerontol Geriatr 23(1):27–37CrossRefPubMedGoogle Scholar
  19. 19.
    Zhao WQ, Chen H, Quon MJ, Alkon DL (2004) Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 490(1–3):71–81.  https://doi.org/10.1016/j.ejphar.2004.02.045 CrossRefPubMedGoogle Scholar
  20. 20.
    Stranahan AM (2015) Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience 309:125–139.  https://doi.org/10.1016/j.neuroscience.2015.04.045 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W (2004) Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29(10):1326–1334.  https://doi.org/10.1016/j.psyneuen.2004.04.003 CrossRefPubMedGoogle Scholar
  22. 22.
    Brunner YF, Kofoet A, Benedict C, Freiherr J (2015) Central insulin administration improves odor-cued reactivation of spatial memory in young men. J Clin Endocrinol Metab 100(1):212–219.  https://doi.org/10.1210/jc.2014-3018 CrossRefPubMedGoogle Scholar
  23. 23.
    Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69(1):29–38.  https://doi.org/10.1001/archneurol.2011.233 CrossRefPubMedGoogle Scholar
  24. 24.
    de la Monte SM (2012) Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimer’s disease therapeutics. Aging Health 8(1):61–64.  https://doi.org/10.2217/ahe.11.89 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Freiherr J, Hallschmid M, Frey WH 2nd, Brunner YF, Chapman CD, Holscher C, Craft S, De Felice FG, Benedict C (2013) Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs 27(7):505–514.  https://doi.org/10.1007/s40263-013-0076-8 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Reger MA, Watson GS, Frey WH 2nd, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S (2006) Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 27(3):451–458.  https://doi.org/10.1016/j.neurobiolaging.2005.03.016 CrossRefPubMedGoogle Scholar
  27. 27.
    Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey WH 2nd, Craft S (2008) Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 13(3):323–331CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Apostolatos A, Song S, Acosta S, Peart M, Watson JE, Bickford P, Cooper DR, Patel NA (2012) Insulin promotes neuronal survival via the alternatively spliced protein kinase CdeltaII isoform. J Biol Chem 287(12):9299–9310.  https://doi.org/10.1074/jbc.M111.313080 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Maimaiti S, DeMoll C, Anderson KL, Griggs RB, Taylor BK, Porter NM, Thibault O (2015) Short-lived diabetes in the young-adult ZDF rat does not exacerbate neuronal Ca2+ biomarkers of aging. Brain Res 1621:214–221.  https://doi.org/10.1016/j.brainres.2014.10.052 CrossRefPubMedGoogle Scholar
  30. 30.
    Salameh TS, Bullock KM, Hujoel IA, Niehoff ML, Wolden-Hanson T, Kim J, Morley JE, Farr SA, Banks WA (2015) Central nervous system delivery of intranasal insulin: mechanisms of uptake and effects on cognition. J Alzheimers Dis 47(3):715–728.  https://doi.org/10.3233/JAD-150307 CrossRefPubMedGoogle Scholar
  31. 31.
    Brini M, Carafoli E (2009) Calcium pumps in health and disease. Physiol Rev 89(4):1341–1378.  https://doi.org/10.1152/physrev.00032.2008 CrossRefPubMedGoogle Scholar
  32. 32.
    Clapham DE (2007) Calcium signaling. Cell 131(6):1047–1058.  https://doi.org/10.1016/j.cell.2007.11.028 CrossRefPubMedGoogle Scholar
  33. 33.
    Frazier HN, Maimaiti S, Anderson KL, Brewer LD, Gant JC, Porter NM, Thibault O (2017) Calcium’s role as nuanced modulator of cellular physiology in the brain. Biochem Biophys Res Commun 483(4):981–987.  https://doi.org/10.1016/j.bbrc.2016.08.105 CrossRefPubMedGoogle Scholar
  34. 34.
    Jiang L, Bechtel MD, Galeva NA, Williams TD, Michaelis EK, Michaelis ML (2012) Decreases in plasma membrane Ca2+-ATPase in brain synaptic membrane rafts from aged rats. J Neurochem 123(5):689–699.  https://doi.org/10.1111/j.1471-4159.2012.07918.x CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Michaelis EK, Michaelis ML, Chang HH, Kitos TE (1983) High affinity Ca2+-stimulated Mg2+-dependent ATPase in rat brain synaptosomes, synaptic membranes, and microsomes. J Biol Chem 258(10):6101–6108PubMedGoogle Scholar
  36. 36.
    Michaelis ML, Michaelis EK (1981) Ca++ fluxes in resealed synaptic plasma membrane vesicles. Life Sci 28(1):37–45CrossRefPubMedGoogle Scholar
  37. 37.
    Schmidt N, Kollewe A, Constantin CE, Henrich S, Ritzau-Jost A, Bildl W, Saalbach A, Hallermann S, Kulik A, Fakler B, Schulte U (2017) Neuroplastin and basigin are essential auxiliary subunits of plasma membrane Ca2+-ATPases and key regulators of Ca2+ clearance. Neuron 96(4):827–838 e829.  https://doi.org/10.1016/j.neuron.2017.09.038 CrossRefPubMedGoogle Scholar
  38. 38.
    Wang X, Michaelis EK (2010) Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2:12.  https://doi.org/10.3389/fnagi.2010.00012 PubMedPubMedCentralGoogle Scholar
  39. 39.
    Khachaturian ZS (1989) The role of calcium regulation in brain aging: reexamination of a hypothesis. Aging (Milano) 1(1):17–34Google Scholar
  40. 40.
    Landfield PW (1987) ‘Increased calcium-current’ hypothesis of brain aging. Neurobiol Aging 8(4):346–347CrossRefPubMedGoogle Scholar
  41. 41.
    Gant JC, Sama MM, Landfield PW, Thibault O (2006) Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+-induced Ca2+ release. J Neurosci 26(13):3482–3490.  https://doi.org/10.1523/JNEUROSCI.4171-05.2006 CrossRefPubMedGoogle Scholar
  42. 42.
    Kumar A, Foster TC (2005) Intracellular calcium stores contribute to increased susceptibility to LTD induction during aging. Brain Res 1031(1):125–128.  https://doi.org/10.1016/j.brainres.2004.10.023 CrossRefPubMedGoogle Scholar
  43. 43.
    Murchison D, McDermott AN, Lasarge CL, Peebles KA, Bizon JL, Griffith WH (2009) Enhanced calcium buffering in F344 rat cholinergic basal forebrain neurons is associated with age-related cognitive impairment. J Neurophysiol 102(4):2194–2207.  https://doi.org/10.1152/jn.00301.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Thibault O, Hadley R, Landfield PW (2001) Elevated postsynaptic [Ca2+]i and L-type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J Neurosci 21(24):9744–9756PubMedGoogle Scholar
  45. 45.
    Thibault O, Landfield PW (1996) Increase in single L-type calcium channels in hippocampal neurons during aging. Science 272(5264):1017–1020CrossRefPubMedGoogle Scholar
  46. 46.
    Pancani T, Anderson KL, Brewer LD, Kadish I, DeMoll C, Landfield PW, Blalock EM, Porter NM, Thibault O (2013) Effect of high-fat diet on metabolic indices, cognition, and neuronal physiology in aging F344 rats. Neurobiol Aging 34(8):1977–1987.  https://doi.org/10.1016/j.neurobiolaging.2013.02.019 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Maimaiti S, Anderson KL, DeMoll C, Brewer LD, Rauh BA, Gant JC, Blalock EM, Porter NM, Thibault O (2016) Intranasal insulin improves age-related cognitive deficits and reverses electrophysiological correlates of brain aging. J Gerontol A 71(1):30–39.  https://doi.org/10.1093/gerona/glu314 CrossRefGoogle Scholar
  48. 48.
    Wilkins HM, Harris JL, Carl SM, Lu EL, Eva Selfridge J, Roy J, Hutfles N, Koppel L, Morris S, Burns J, Michaelis JM, Michaelis ML, Brooks EK, Swerdlow WM RH (2014) Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. Hum Mol Genet 23(24):6528–6541.  https://doi.org/10.1093/hmg/ddu371 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Lebwohl DE, Nunez I, Chan M, Rosen OM (1991) Expression of inducible membrane-anchored insulin receptor kinase enhances deoxyglucose uptake. J Biol Chem 266(1):386–390PubMedGoogle Scholar
  50. 50.
    Pancani T, Anderson KL, Porter NM, Thibault O (2011) Imaging of a glucose analog, calcium and NADH in neurons and astrocytes: dynamic responses to depolarization and sensitivity to pioglitazone. Cell Calcium 50(6):548–558.  https://doi.org/10.1016/j.ceca.2011.09.002 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Pancani T, Phelps JT, Searcy JL, Kilgore MW, Chen KC, Porter NM, Thibault O (2009) Distinct modulation of voltage-gated and ligand-gated Ca2+ currents by PPAR-gamma agonists in cultured hippocampal neurons. J Neurochem 109(6):1800–1811.  https://doi.org/10.1111/j.1471-4159.2009.06107.x CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Porter NM, Thibault O, Thibault V, Chen KC, Landfield PW (1997) Calcium channel density and hippocampal cell death with age in long-term culture. J Neurosci 17(14):5629–5639PubMedGoogle Scholar
  53. 53.
    Furler S, Paterna JC, Weibel M, Bueler H (2001) Recombinant AAV vectors containing the foot and mouth disease virus 2A sequence confer efficient bicistronic gene expression in cultured cells and rat substantia nigra neurons. Gene Ther 8(11):864–873.  https://doi.org/10.1038/sj.gt.3301469 CrossRefPubMedGoogle Scholar
  54. 54.
    Mizuguchi H, Xu Z, Ishii-Watabe A, Uchida E, Hayakawa T (2000) IRES-dependent second gene expression is significantly lower than cap-dependent first gene expression in a bicistronic vector. Mol Ther 1(4):376–382.  https://doi.org/10.1006/mthe.2000.0050 CrossRefPubMedGoogle Scholar
  55. 55.
    Bodhinathan K, Kumar A, Foster TC (2010) Redox sensitive calcium stores underlie enhanced after hyperpolarization of aged neurons: role for ryanodine receptor mediated calcium signaling. J Neurophysiol 104(5):2586–2593.  https://doi.org/10.1152/jn.00577.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Disterhoft JF, Thompson LT, Moyer JR Jr, Mogul DJ (1996) Calcium-dependent afterhyperpolarization and learning in young and aging hippocampus. Life Sci 59(5–6):413–420CrossRefPubMedGoogle Scholar
  57. 57.
    Kumar A, Foster TC (2004) Enhanced long-term potentiation during aging is masked by processes involving intracellular calcium stores. J Neurophysiol 91(6):2437–2444.  https://doi.org/10.1152/jn.01148.2003 CrossRefPubMedGoogle Scholar
  58. 58.
    Norris CM, Halpain S, Foster TC (1998) Reversal of age-related alterations in synaptic plasticity by blockade of L-type Ca2+ channels. J Neurosci 18(9):3171–3179PubMedGoogle Scholar
  59. 59.
    Thibault O, Porter NM, Landfield PW (1993) Low Ba2+ and Ca2+ induce a sustained high probability of repolarization openings of L-type Ca2+ channels in hippocampal neurons: physiological implications. Proc Natl Acad Sci USA 90(24):11792–11796CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Landfield PW, Pitler TA (1984) Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science 226(4678):1089–1092CrossRefPubMedGoogle Scholar
  61. 61.
    Wu WW, Oh MM, Disterhoft JF (2002) Age-related biophysical alterations of hippocampal pyramidal neurons: implications for learning and memory. Ageing Res Rev 1(2):181–207CrossRefPubMedGoogle Scholar
  62. 62.
    Berhanu P, Kolterman OG, Baron A, Tsai P, Olefsky JM, Brandenburg D (1983) Insulin receptors in isolated human adipocytes. Characterization by photoaffinity labeling and evidence for internalization and cellular processing. J Clin Investig 72(6):1958–1970.  https://doi.org/10.1172/JCI111160 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Sonne O, Simpson IA (1984) Internalization of insulin and its receptor in the isolated rat adipose cell. Time-course and insulin concentration dependency. Biochim Biophys Acta 804(4):404–413CrossRefPubMedGoogle Scholar
  64. 64.
    Standaert ML, Pollet RJ (1984) Equilibrium model for insulin-induced receptor down-regulation. Regulation of insulin receptors in differentiated BC3H-1 myocytes. J Biol Chem 259(4):2346–2354PubMedGoogle Scholar
  65. 65.
    Wang CC, Sonne O, Hedo JA, Cushman SW, Simpson IA (1983) Insulin-induced internalization of the insulin receptor in the isolated rat adipose cell. Detection of the internalized 138-kilodalton receptor subunit using a photoaffinity 125I-insulin. J Biol Chem 258(8):5129–5134PubMedGoogle Scholar
  66. 66.
    Boyd FT Jr, Raizada MK (1983) Effects of insulin and tunicamycin on neuronal insulin receptors in culture. Am J Physiol 245(3):C283-287CrossRefGoogle Scholar
  67. 67.
    Lee CC, Huang CC, Wu MY, Hsu KS (2005) Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. J Biol Chem 280(18):18543–18550.  https://doi.org/10.1074/jbc.M414112200 CrossRefPubMedGoogle Scholar
  68. 68.
    Kim EY, Dryer SE (2011) Effects of insulin and high glucose on mobilization of slo1 BKCa channels in podocytes. J Cell Physiol 226(9):2307–2315.  https://doi.org/10.1002/jcp.22567 CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Benomar Y, Naour N, Aubourg A, Bailleux V, Gertler A, Djiane J, Guerre-Millo M, Taouis M (2006) Insulin and leptin induce Glut4 plasma membrane translocation and glucose uptake in a human neuronal cell line by a phosphatidylinositol 3-kinase- dependent mechanism. Endocrinology 147(5):2550–2556.  https://doi.org/10.1210/en.2005-1464 CrossRefPubMedGoogle Scholar
  70. 70.
    Biessels GJ, Reagan LP (2015) Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 16(11):660–671.  https://doi.org/10.1038/nrn4019 CrossRefPubMedGoogle Scholar
  71. 71.
    Grillo CA, Piroli GG, Lawrence RC, Wrighten SA, Green AJ, Wilson SP, Sakai RR, Kelly SJ, Wilson MA, Mott DD, Reagan LP (2015) Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes 64(11):3927–3936.  https://doi.org/10.2337/db15-0596 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS (2010) Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem 93(4):546–553.  https://doi.org/10.1016/j.nlm.2010.02.002 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, Kondo T, Alber J, Galldiks N, Kustermann E, Arndt S, Jacobs AH, Krone W, Kahn CR, Bruning JC (2004) Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci USA 101(9):3100–3105.  https://doi.org/10.1073/pnas.0308724101 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Werner ED, Lee J, Hansen L, Yuan M, Shoelson SE (2004) Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302. J Biol Chem 279(34):35298–35305.  https://doi.org/10.1074/jbc.M405203200 CrossRefPubMedGoogle Scholar
  75. 75.
    Blalock EM, Phelps JT, Pancani T, Searcy JL, Anderson KL, Gant JC, Popovic J, Avdiushko MG, Cohen DA, Chen KC, Porter NM, Thibault O (2010) Effects of long-term pioglitazone treatment on peripheral and central markers of aging. PLoS ONE 5(4):e10405.  https://doi.org/10.1371/journal.pone.0010405 CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Sartorius T, Peter A, Heni M, Maetzler W, Fritsche A, Haring HU, Hennige AM (2015) The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier? PLoS ONE 10(5):e0126804.  https://doi.org/10.1371/journal.pone.0126804 CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Stanley M, Macauley SL, Caesar EE, Koscal LJ, Moritz W, Robinson GO, Roh J, Keyser J, Jiang H, Holtzman DM (2016) The effects of peripheral and central high insulin on brain insulin signaling and amyloid-beta in young and old APP/PS1 mice. J Neurosci 36(46):11704–11715.  https://doi.org/10.1523/JNEUROSCI.2119-16.2016 CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Abbott MA, Wells DG, Fallon JR (1999) The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J Neurosci 19(17):7300–7308PubMedGoogle Scholar
  79. 79.
    Chiu SL, Chen CM, Cline HT (2008) Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 58(5):708–719.  https://doi.org/10.1016/j.neuron.2008.04.014 CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Zhao WQ, Alkon DL (2001) Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 177(1–2):125–134CrossRefPubMedGoogle Scholar
  81. 81.
    Michaelis ML, Jiang L, Michaelis EK (2017) Isolation of synaptosomes, synaptic plasma membranes, and synaptic junctional complexes. Methods Mol Biol 1538:107–119.  https://doi.org/10.1007/978-1-4939-6688-2_9 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • H. N. Frazier
    • 1
  • K. L. Anderson
    • 1
  • S. Maimaiti
    • 1
  • A. O. Ghoweri
    • 1
  • S. D. Kraner
    • 3
  • G. J. Popa
    • 2
  • K. K. Hampton
    • 1
  • M. D. Mendenhall
    • 2
  • C. M. Norris
    • 3
  • R. J. Craven
    • 1
  • O. Thibault
    • 1
  1. 1.Department of Pharmacology and Nutritional SciencesUniversity of Kentucky Medical Center, UKMCLexingtonUSA
  2. 2.Department of Molecular and Cellular BiochemistryUniversity of Kentucky Medical Center, UKMCLexingtonUSA
  3. 3.Sanders Brown Center on AgingUniversity of Kentucky Medical Center, UKMCLexingtonUSA

Personalised recommendations