Cholesterol and Its Role in Synaptic Transmission

  • Tatiana Borisova
Part of the SpringerBriefs in Neuroscience book series (BRIEFSNEUROSCI, volume 12)


Certain level of membrane cholesterol, which is an abundant constituent of eukaryotic membranes, is very important for normal functioning of a number of membrane proteins involved in synaptic transmission, such as ion channels, pumps, receptors, and transporters, while the alterations in cholesterol content change the property of membranes and the activity of these proteins. Moreover, cholesterol deficiency has been implicated in the pathogenesis of several neurodegenerative disorders.


Synaptic Vesicle Cholesterol Content Glutamate Transporter Glutamate Uptake Membrane Cholesterol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Allen JA, Halverson-Tamboli RA, Rasenick MM (2007) Lipid rafts microdomains and neurotransmitter signaling. Nat Rev Neurosci 8:128–140PubMedCrossRefGoogle Scholar
  2. Barnes K, Ingram JC, Bennett MDM et al (2004) Methyl-beta-cyclodextrin stimulates glucose uptake in Clone 9 cells: a possible role for lipid rafts. Biochem J 378:343–351PubMedCrossRefPubMedCentralGoogle Scholar
  3. Beurrier C, Bonvento G, Kerkerian-Le Goff L, Gubellini P (2009) Role of glutamate transporters in corticostriatal synaptic transmission. Neuroscience 158:1608–1615PubMedCrossRefGoogle Scholar
  4. Bonini M, Rossi S, Karlsson G, Almgren M, Lo Nostro P, Baglioni P (2006) Self-assembly of beta-cyclodextrin in water. Part 1: Cryo-TEM and dynamic and static light scattering. Langmuir 22:1478–1484PubMedCrossRefGoogle Scholar
  5. Brasnjo G, Otis T (2001) Neuronal glutamate transporters control activation of postsynaptic metabotropic glutamate receptor and influence cerebellar long-term depression. Neuron 31:607–616PubMedCrossRefGoogle Scholar
  6. Burger K, Gimpl G, Fahrenholz F (2000) Regulation of receptor function by cholesterol. Cell Mol Life Sci 57:1577–1592PubMedCrossRefGoogle Scholar
  7. Butchbach M, Tian G, Guo H, Lin CG (2004) Association of excitatory amino acid transporters, especially EAAT2, with cholesterol-rich lipid raft microdomains. J Biol Chem 279:34388–34396PubMedCrossRefGoogle Scholar
  8. Cavelier P, Attwell D (2005) Tonic release of glutamate by a DIDS-sensitive mechanism in rat hippocampal slices. J Physiol 564:397–410PubMedCrossRefPubMedCentralGoogle Scholar
  9. Cevc G, Richardsen H (1999) Lipid vesicles and membrane fusion. Adv Drug Deliv Rev 38:207–232PubMedCrossRefGoogle Scholar
  10. Chattopadhyay A, Paila YD (2007) Lipid-protein interactions, regulation and dysfunction of brain cholesterol. Biochem Biophys Res Commun 354:627–633PubMedCrossRefGoogle Scholar
  11. Cho WJ, Jeremic A, Jin H et al (2007) Neuronal fusion pore assembly requires membrane cholesterol. Cell Biol Int 31:1301–1308PubMedCrossRefPubMedCentralGoogle Scholar
  12. Chou YC, Lin SB, Tsai LH, Tsai HI, Lin CM (2003) Cholesterol deficiency increases the vulnerability of hippocampal glia in primary culture to glutamate-induced excitotoxicity. Neurochem Int 43:197–209PubMedCrossRefGoogle Scholar
  13. Churchward MA, Rogasevskaia T, Hofgen J et al (2005) Cholesterol facilitates the native mechanism of Ca2+-triggerted membrane fusion. J Cell Sci 118:4833–4848PubMedCrossRefGoogle Scholar
  14. Crockett EL (1998) Cholesterol function in plasma membranes from ectotherms: membrane-specific roles in adaptation to temperature. Am Zool 38:291–304Google Scholar
  15. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105PubMedCrossRefGoogle Scholar
  16. Dalskov SM, Immerdal L, Niels-Christiansen LL, Hansen GH, Schousboe A, Danielsen EM (2005) Lipid raft localization of GABA A receptor and Na+, K+-ATPase in discrete microdomain clusters in rat cerebellar granule cells. Neurochem Int 46:489–499PubMedCrossRefGoogle Scholar
  17. Deutsch JW, Kelly RB (1981) Lipids of synaptic vesicles: relevance to the mechanism of membrane fusion. Biochemistry 20:378–385PubMedCrossRefGoogle Scholar
  18. Dietschy JM, Turley SD (2001) Cholesterol metabolism in the brain. Curr Opin Lipidol 12:105–112PubMedCrossRefGoogle Scholar
  19. Eroglu C, Bruger B, Wieland F et al (2003) Glutamate-binding affinity of Drosophila metabotropic glutamate receptor is modulated by association with lipid rafts. Proc Natl Acad Sci USA 100:10219–10224PubMedCrossRefPubMedCentralGoogle Scholar
  20. Fong TM, McNamee MG (1986) Correlation between acetylcholine receptor function and structural properties of membranes. Biochemistry 25:830–840PubMedCrossRefGoogle Scholar
  21. González MI, Susarla BT, Fournier KM (2007) Constitutive endocytosis and recycling of the neuronal glutamate transporter, excitatory amino acid carrier 1. J Neurochem 103:1917–1931PubMedCrossRefGoogle Scholar
  22. Hering H, Lin CC, Sheng M (2003) Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. J Neurosci 23:3262–3271PubMedGoogle Scholar
  23. Hill W, An B, Johnson J (2002) Endogenously expressed epithelial sodium channel is present in lipid rafts in A6 cells. J Biol Chem 277:33541–33544PubMedCrossRefGoogle Scholar
  24. Jadot M, Andrianaivo F, Dubois F, Wattiaux R (2001) Effects of methylcyclodextrin on lysosomes. Eur J Biochem 268:1392–1399PubMedCrossRefGoogle Scholar
  25. Jennings LJ, Xu QW, Firth TA (1999) Cholesterol inhibits spontaneous action potentials and calcium currents in guinea pig gallbladder smooth muscle. Am J Physiol 277:1017–1026Google Scholar
  26. Kato N, Nakanishi M, Hirashima N (2003) Cholesterol depletion inhibits store-operated calcium currents and exocytotic membrane fusion in RBL-2H3 cells. Biochemistry 42:11808–11814PubMedCrossRefGoogle Scholar
  27. Kroes J, Ostwald R (1971) Erythrocyte membranes—effect of increased cholesterol content on permeability. Biochim Biophys Acta 249:647–650PubMedCrossRefGoogle Scholar
  28. Lang T, Bruns D, Wenzel D et al (2001) SNAREs are concentrated in cholesterol-dependent clusters that define docking and fusion sites for exocytosis. EMBO J 20:2202–2213PubMedCrossRefPubMedCentralGoogle Scholar
  29. Lange Y, Ye J, Steck TL (2004) How cholesterol homeostasis is regulated by plasma membrane cholesterol in excess of phospholipids. Proc Natl Acad Sci USA 101(32):11664–11667PubMedCrossRefPubMedCentralGoogle Scholar
  30. Lange Y, Ye J, Steck TL (2005) Activation of membrane cholesterol by displacement from phospholipids. J Biol Chem 280:36126–36131PubMedCrossRefGoogle Scholar
  31. Launikonis BS, Stephenson DG (2001) Effects of membrane cholesterol manipulation on excitation-contraction coupling in skeletal muscle of the toad. J Physiol 534:71–85PubMedCrossRefPubMedCentralGoogle Scholar
  32. Levitan I, Christian AE, Tulenko TN, Rothblat GH (2000) Membrane cholesterol content modulates activation of volume-regulated anion current in bovine endothelial cells. J Gen Physiol 115:405–416PubMedCrossRefPubMedCentralGoogle Scholar
  33. Martens J, O`Connell K, Tamkun M (2004) Targeting of ion channels to membrane microdomains: localization of Kv channels to lipid rafts. Trends Pharmacol Sci 25:16–21PubMedCrossRefGoogle Scholar
  34. Mauch DH, Nägler K, Schumacher S et al (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354–1357PubMedCrossRefGoogle Scholar
  35. Messner M, Kurkov SV, Jansook P, Loftsson T (2010) Self-assembled cyclodextrin aggregates and nanoparticles. Int J Pharm 387:199–208PubMedCrossRefGoogle Scholar
  36. Mitter D, Reisinger C, Hinz B (2003) The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content. J Neurochem 84:35–42PubMedCrossRefGoogle Scholar
  37. Miyajima K, Sawada M, Nakagaki M (1983) Viscosity B-coefficients, apparent molar volumes, and activity-coefficients for alpha-cyclodextrin and gamma-cyclodextrin in aqueous-solutions. Bull Chem Soc Jpn 56:3556–3560CrossRefGoogle Scholar
  38. Miyajima K, Mukai T, Nakagaki M, Otagiri M, Uekama K (1986) Activity-coefficients of dimethyl-beta-cyclodextrin in aqueous-solutions. Bull Chem Soc Jpn 59:643–644CrossRefGoogle Scholar
  39. Pfrieger FW (2003) Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol Life Sci 60:1158–1171PubMedGoogle Scholar
  40. Rodal SK, Skretting G, Garred O, Vilhardt F, van Deurs B, Sandvig K (1999) Extraction of cholesterol with methyl-beta-cyclodextrin perturbs formation of clathrin-coated endocytic vesicles. Mol Biol Cell 10:961–974PubMedCrossRefPubMedCentralGoogle Scholar
  41. Rohrbough J, Broadie K (2005) Lipid regulation of the synaptic vesicle cycle. Nat Rev Neurosci 6:139–150PubMedCrossRefGoogle Scholar
  42. Romanenko VG, Rothblat GH, Levitan I (2002) Modulation of endothelial inward-rectifier K+ current by optical isomers of cholesterol. Biophys J 83:3211–3222PubMedCrossRefPubMedCentralGoogle Scholar
  43. Salaun C, James DJ, Chamberlain LH (2004) Lipid rafts and the regulation of exocytosis. Traffic 5:1–10CrossRefGoogle Scholar
  44. Salaun C, Gould GW, Chamberlain LH (2005) The SNARE proteins SNAP-25 and SNAP-23 display different affinities for lipid rafts in PC12 cells. Regulation by distinct cysteine-rich domains. J Biol Chem 280(2):1236–1240CrossRefGoogle Scholar
  45. Singh M, Sherma R, Banerjee U (2002) Biotechnological application of cyclodextrins. Biotechnol Adv 20:341–359PubMedCrossRefGoogle Scholar
  46. Sooksawate T, Simmonds MA (2001) Effects of membrane cholesterol on the sensitivity of the GABA(A) receptor to GABA in acutely dissociated rat hippocampal neurones. Neuropharmacology 40:178–184PubMedCrossRefGoogle Scholar
  47. Steck TL, Ye J, Lange Y (2002) Probing red cell membrane cholesterol movement with cyclopdextrin. Biophys J 83:2118–2125PubMedCrossRefPubMedCentralGoogle Scholar
  48. Subtil A, Gaidarov I, Kobylarz K et al (1999) Acute cholesterol depletion inhibits clathrin-coated pit budding. Proc Natl Acad Sci USA 96:6775–6780PubMedCrossRefPubMedCentralGoogle Scholar
  49. Taverna E, Saba E, Rowe J et al (2004) Role of lipid microdomains in P/Q-type calcium channel (Cav2.1) clustering and function in presynaptic membranes. J Biol Chem 279:5127–5134PubMedCrossRefGoogle Scholar
  50. Thiele C, Hannah MJ, Fahrenholz F, Huttner WB (2000) Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nat Cell Biol 2:42–49PubMedCrossRefGoogle Scholar
  51. Tsai HI, Tsai LH, Chen MY et al (2006) Cholesterol deficiency perturbs actin signaling and glutamate homeostasis in hippocampal astrocytes. Brain Res 1104:27–38PubMedCrossRefGoogle Scholar
  52. Wasser CR, Ertunc M, Liu X et al (2007) Cholesterol-dependent balance between evoked and spontaneous vesicle recycling. J Physiol 579(2):413–429PubMedCrossRefPubMedCentralGoogle Scholar
  53. Xia F, Gao X, Kwan E et al (2004) Disruption of pancreatic β-cells lipid rafts modifies Kv2.1 channel gating and insulin exocyrtosis. J Biol Chem 279:24685–24691PubMedCrossRefGoogle Scholar
  54. Xia F, Leung YM, Gaisano G et al (2007) Targeting of Kv4, Cav1.2 and SNARE proteins to cholesterol-rich lipid rafts in pancreatic a-cells: effects on glucagons stimulus-secretion coupling. Endocrinology 148:2157–2167PubMedCrossRefGoogle Scholar
  55. Yancey PG, Rodrigueza WV, Kilsdonk EP et al (1996) Cellular cholesterol efflux mediated by cyclodextrins. J Biol Chem 271:16026–16034PubMedCrossRefGoogle Scholar
  56. Zamir O, Charlton MP (2006) Cholesterol and synaptic transmitter release at crayfish neuromuscular junctions. J Physiol 571:83–99PubMedCrossRefPubMedCentralGoogle Scholar
  57. Zidovetzki R, Levitan I (2007) Use of cyclodextrins to manipulatre plasma membrane cholesterol content: evidence, misconceptions and control strategies. Biochim Biophys Acta 1768:1311–1324PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Tatiana Borisova
    • 1
  1. 1.Department of Neurochemistry Palladin Institute of BiochemistryNational Academy of Sciences of UkraineKievUkraine

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