Involvement of Cdk5 in Synaptic Plasticity, and Learning and Memory

  • Florian Plattner
  • K. Peter Giese
  • Marco Angelo


Cdk5 has been demonstrated to be one of the most diversely functional kinases within neurons. It is unsurprising then that recent advances implicate Cdk5 in synaptic plasticity, and learning and memory. In this chapter, we summarize the data that reveal the involvement of Cdk5 in mnemonic processes on molecular as well as cellular levels and relate these findings to its emerging function in learning and memory. From amongst the impressive range of candidate mechanisms by which Cdk5 might influence mnemonic processes, we pay particular attention to mechanisms with well-established function in both, synaptic plasticity, and learning and memory, including NMDA receptor modulation, transcriptional regulation and organization of synaptic structures. We aim to show that Cdk5 is uniquely placed amongst kinases to orchestrate the multi-level processes inherent in learning and memory owing to its integral role in many neuronal functions.


Synaptic Plasticity Morris Water Maze Cdk5 Activity NMDAR Subunit Contextual Fear Memory 
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. Agarwal-Mawal A, Paudel HK. (2001) Neuronal Cdc2-like protein kinase (Cdk5/p25) is associated with protein phosphatase 1 and phosphorylates inhibitor-2. J. Biol. Chem. 276: 23712–23718.PubMedCrossRefGoogle Scholar
  2. Anagnostaras SG, Gale GD, Fanselow MS. (2001) Hippocampus and contextual fear conditioning: recent controversies and advances. Hippocampus 11: 8–17.PubMedCrossRefGoogle Scholar
  3. Angelo M, Plattner F, Irvine EE, Giese KP. (2003) Improved reversal learning and altered fear conditioning in transgenic mice with regionally restricted p25 expression. Eur. J. Neurosci. 18: 423–431.PubMedCrossRefGoogle Scholar
  4. Angelo M, Plattner F, Giese KP. (2006) Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. J. Neurochem. 99: 353–370.PubMedCrossRefGoogle Scholar
  5. Arimura N, Ménager C, Kawano Y, Yoshimura T, Kawabata S, Hattori A, Fukata Y, Amano M, Goshima Y, Inagaki M, Morone N, Usukura J, Kaibuchi K. (2005) Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol. Cell. Biol. 25:9973–9984.PubMedCrossRefGoogle Scholar
  6. Barclay JW, Aldea M, Craig TJ, Morgan A, Burgoyne RD. (2004) Regulation of the fusion pore conductance during exocytosis by cyclin-dependent kinase 5. J. Biol. Chem. 279: 41495–41503.PubMedCrossRefGoogle Scholar
  7. Beffert U, Weeber EJ, Morfini G, Ko J, Brady ST, Tsai LH, Sweatt JD, Herz J. (2004) Reelin and cyclin-dependent kinase 5-dependent signals cooperate in regulating neuronal migration and synaptic transmission. J. Neurosci. 24: 1897–1906.PubMedCrossRefGoogle Scholar
  8. Bibb JA, Snyder GL, Nishi A, et al. (1999) Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402: 669–671.PubMedCrossRefGoogle Scholar
  9. Bibb JA, Nishi A, O'Callaghan JP, et al. (2001) Phosphorylation of protein phosphatase inhibitor-1 by Cdk5. J. Biol. Chem. 276: 14490–14497.PubMedGoogle Scholar
  10. Brown M, Jacobs T, Eickholt B, Ferrari G, Teo M, Monfries C, Qi RZ, Leung T, Lim L, Hall C. (2004) Alpha2-chimaerin, cyclin-dependent Kinase 5/p35, and its target collapsin response mediator protein-2 are essential components in semaphorin 3A-induced growth-cone collapse. J. Neurosci. 24: 8994–9004.PubMedCrossRefGoogle Scholar
  11. Buraei Z, Anghelescu M, Elmslie KS. (2005) Slowed N-type calcium channel (CaV2.2) deactivation by the cyclin-dependent kinase inhibitor roscovitine. Biophys. J. 89: 1681–1691.PubMedCrossRefGoogle Scholar
  12. Buraei Z, Schofield G, Elmslie KS (2007) Roscovitine differentially affects CaV2 and Kv channels by binding to the open state. Neuropharmacology. 52: 883–894.PubMedCrossRefGoogle Scholar
  13. Causeret F, Jacobs T, Terao M, Heath O, Hoshino M, Nikolic M. (2007) Neurabin-I is phosphorylated by Cdk5: implications for neuronal morphogenesis and cortical migration. Mol. Biol. Cell. 18: 4327–4342.PubMedCrossRefGoogle Scholar
  14. Cheng Q, Sasaki Y, Shoji M, Sugiyama Y, Tanaka H, Nakayama T, Mizuki N, Nakamura F, Takei K, Goshima Y. (2003) Cdk5/p35 and Rho-kinase mediate ephrin-A5-induced signaling in retinal ganglion cells. Mol. Cell. Neurosci. 24: 632–645.PubMedCrossRefGoogle Scholar
  15. Chergui K, Svenningsson P, Greengard P. (2004) Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum. Proc. Natl. Acad. Sci. U.S.A. 101: 2191–2196.PubMedCrossRefGoogle Scholar
  16. Cheung ZH, Chin WH, Chen Y, Ng YP, Ip NY (2007) Cdk5 is involved in BDNF-stimulated dendritic growth in hippocampal neurons. PLoS Biol. 5: e63PubMedCrossRefGoogle Scholar
  17. Cicero S, Herrup K. (2005) Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. J. Neurosci. 25: 9658–9668.PubMedCrossRefGoogle Scholar
  18. Cole AR, Causeret F, Yadirgi G, Hastie CJ, McLauchlan H, McManus EJ, Hernández F, Eickholt BJ, Naikolic M, Sutherland C. (2006) Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. J. Biol. Chem. 281: 16591–16598.PubMedCrossRefGoogle Scholar
  19. Cruz JC, Kim D, Moy LY, Dobbin MM, Sun X, Bronson RT, Tsai LH. (2006) p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J. Neurosci. 26: 10536–10541.PubMedCrossRefGoogle Scholar
  20. Dhavan R, Greer PL, Morabito MA, Orlando LR, Tsai LH. (2002) The cyclin-dependent kinase 5 activators p35 and p39 interact with the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II and alpha-actinin-1 in a calcium-dependent manner. J. Neurosci. 22: 7879–7891.PubMedGoogle Scholar
  21. D'Hooge R, De Deyn P.P. (2001) Applications of the Morris water maze in the study of learning and memory. Brain. Res. Brain. Res. Rev. 36: 60–90.PubMedCrossRefGoogle Scholar
  22. Evans GJO, Cousin MA. (2007) Activity-dependent control of slow synaptic vesicle endocytosis by cyclin-dependent kinase 5. J. Neurosci. 27: 401–411.PubMedCrossRefGoogle Scholar
  23. Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J. (2002) Cyclin-dependent kinase 5 is required for associative learning. J. Neurosci. 22: 3700–3707.PubMedGoogle Scholar
  24. Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J. (2003) Regulation of contextual fear conditioning by baseline and inducible septo-hippocampal cyclin-dependent kinase 5. Neuropharmacology 44: 1089–1099.PubMedCrossRefGoogle Scholar
  25. Fischer A, Sananbenesi F, Pang PT, Lu B, Tsai LH. (2005) Opposing Roles of Transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48: 825–838.PubMedCrossRefGoogle Scholar
  26. Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai L.H. (2007) Recovery of learning and memory is associated with chromatin remodelling. Nature 447: 178–182.PubMedCrossRefGoogle Scholar
  27. Fletcher AI, Shuang R, Giovannucci DR, Zhang L, Bittner MA, Stuenkel EL. (1999) Regulation of exocytosis by cyclin-dependent kinase 5 via phosphorylation of Munc18. J. Biol. Chem. 274: 4027–4035.PubMedCrossRefGoogle Scholar
  28. Floyd SR, Porro EB, Slepnev VI, Ochoa GC, Tsai LH, De Camilli P. (2001) Amphiphysin 1 binds the cyclin-dependent kinase (Cdk) 5 regulatory subunit p35 and is phosphorylated by cdk5 and cdc2. J. Biol. Chem. 276: 8104–8110.PubMedCrossRefGoogle Scholar
  29. Fu AKY, Fu WY, Cheung J, Tsim KW, IP FC, Wang J.H, Ip NY (2001) Cdk5 is involved in neuregulin-induced AchR expression at the neuromuscular junction. Nat Neurosci 4: 374–381.PubMedCrossRefGoogle Scholar
  30. Fu AK., Fu WY, Ng AK, Chien WW, Ng YP, Wang JH, Ip NY. (2004) Cyclin-dependent kinase 5 phosphorylates signal transducer and activator of transcription 3 and regulates its transcriptional activity. Proc. Natl. Acad. Sci. U.S.A. 101: 6728–6733.PubMedCrossRefGoogle Scholar
  31. Fu AK, Ip FC, Fu WY, Cheung J, Wang JH, Yung WH, Ip NY. (2005) Aberrant motor axon projection, acetylcholine receptor clustering, and neurotransmission in cyclin-dependent kinase 5 null mice. Proc. Natl. Acad. Sci. U.S.A. 102: 15224–15229.PubMedCrossRefGoogle Scholar
  32. Fu X, Choi YK, Qu D, Yu Y, Cheung NS, Qi RZ. (2006) Identification of nuclear import mechanisms for the neuronal Cdk5 activator. J. Biol. Chem. 281: 39014–39021.PubMedCrossRefGoogle Scholar
  33. Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AK, Greenberg ME, Ip NY (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat. Neurosci. 10: 67–76.PubMedCrossRefGoogle Scholar
  34. Futter M, Uematsu K, Bullock SA, Kim Y, Hemmings HC Jr, Nishi A, Greengard P, Nairn AC. (2005) Phosphorylation of spinophilin by ERK and cyclin-dependent PK 5 (Cdk5). Proc. Natl. Acad. Sci. U.S.A. 102: 3489–3494.PubMedCrossRefGoogle Scholar
  35. Giese KP, Ris L, Plattner F. (2005) Is there a role of the cyclin-dependent kinase 5 activator p25 in Alzheimer's disease? Neuroreport 16: 1725–1730.PubMedCrossRefGoogle Scholar
  36. Gong X, Tang X, Wiedmann M, Wang X, Peng J, Zheng D, Blair LA, Marshall J, Mao Z. (2003) Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron 38: 33–46.PubMedCrossRefGoogle Scholar
  37. Graham ME, Anggono V, Bache N, Larsen MR, Craft GE, Robinson PJ. (2007) The in vivo phosphorylation sites of rat brain dynamin I. J. Biol. Chem. 282: 14695–14707.PubMedCrossRefGoogle Scholar
  38. Harada T, Morooka T, Ogawa S, Nishida E. (2001) ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1. Nat Cell Biol. 3: 453–459.PubMedCrossRefGoogle Scholar
  39. Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA. (2007) Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat. Neurosci. 10: 880–886.PubMedCrossRefGoogle Scholar
  40. Hayashi ML, Choi SY, Rao BS, Jung HY, Lee HK, Zhang D, Chattarji S, Kirkwood A, Tonegawa S. (2004) Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice. Neuron 42: 773–787.PubMedCrossRefGoogle Scholar
  41. Hayashi K, Pan Y, Shu H, Ohshima T, Kansy JW, White CL 3rd, Tamminga CA, Sobel A, Curmi PA, Mikoshiba K, Bibb JA. (2006) Phosphorylation of the tubulin-binding protein, stathmin, by Cdk5 and MAP kinases in the brain. J. Neurochem. 99: 237–250.PubMedCrossRefGoogle Scholar
  42. Hlavanda E, Klement E, Kókai E, Kovács J, Vincze O, Tökési N, Orosz F, Medzihradszky KF, Dombrádi V, Ovádi J. (2007) Phosphorylation blocks the activity of tubulin polymerization-promoting protein (TPPP): identification of sites targeted by different kinases. J. Biol. Chem. 282: 29531–29539.PubMedCrossRefGoogle Scholar
  43. Horiuchi Y, Asada A, Hisanaga S, Toh-e A, Nishizawa M. (2006) Identifying novel substrates for mouse Cdk5 kinase using the yeast Saccharomyces cerevisiae. Genes Cells. 11: 1393–1404.PubMedCrossRefGoogle Scholar
  44. Hosokawa T, Saito T, Asada A, Ohshima T, Itakura M, Takahashi M, Fukunaga K, Hisanaga S. (2006) Enhanced activation of Ca2+/calmodulin-dependent protein kinase II upon downregulation of cyclin-dependent kinase 5-p35. J. Neurosci. Res. 84: 747–754.PubMedCrossRefGoogle Scholar
  45. Hou Z, He L, Qi RZ. (2007) Regulation of s6 kinase 1 activation by phosphorylation at ser-411. J. Biol. Chem. 282: 6922–6928.PubMedCrossRefGoogle Scholar
  46. Huang KX, Paudel HK. (2000) Ser67-phosphorylated inhibitor 1 is a potent protein phosphatase 1 inhibitor. Proc. Natl. Acad. Sci. U.S.A. 97: 5824–5829.PubMedCrossRefGoogle Scholar
  47. Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, Greengard P, Kirino Y, Nairn AC, Suzuki T. (2000) Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5. J. Neurochem. 75: 1085–1091.PubMedCrossRefGoogle Scholar
  48. Irvine EE, von Hertzen LSJ, Plattner F, Giese KP. (2006) αCaMKII autophosphorylation: a fast track to memory. Trends Neurosci. 29: 459–465.PubMedCrossRefGoogle Scholar
  49. Kamei H, Saito T, Ozawa M, Fujita Y, Asada A, Bibb JA, Saido TC, Sorimachi H, Hisanaga S. (2007) Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation. J. Biol. Chem. 282: 1687–1694.PubMedCrossRefGoogle Scholar
  50. Kansy JW, Daubner SC, Nishi A et al. (2004) Identification of tyrosine hydroxylase as a physiological substrate for Cdk5. J. Neurochem. 91: 374–384.PubMedCrossRefGoogle Scholar
  51. Kato G, Maeda S. (1999) Neuron-specific Cdk5 kinase is responsible for mitosis-independent phosphorylation of c-Src at Ser75 in human Y79 retinoblastoma cells. J. Biochem. (Tokyo) 126: 957–961.CrossRefGoogle Scholar
  52. Kerokoski P, Suuronen T, Salminen A, Soininen H, Pirttila T. (2004) Both N-methyl-D-aspartate (NMDA) and non-NMDA receptors mediate glutamate-induced cleavage of the cyclin-dependent kinase 5 (Cdk5) activator p35 in cultured rat hippocampal neurons. Neurosci. Lett. 368: 181–185.PubMedCrossRefGoogle Scholar
  53. Kesavapany S, Lau KF, McLoughlin DM, Brownlees J, Ackerley S, Leigh PN, Shaw CE, Miller CC (2001) p35/cdk5 binds and phosphorylates beta-catenin and regulates beta-catenin/presenilin-1 interaction. Eur. J. Neurosci. 13: 241–247.Google Scholar
  54. Kesavapany S, Amin N, Zheng YL et al. (2004) p35/cyclin-dependent kinase 5 phosphorylation of Ras guanine nucleotide releasing factor 2 (RasGRF2) mediates Rac-dependent Extracellular signal-regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated protein 1b distribution in neurons. J. Neurosci. 24: 4421–4431.PubMedCrossRefGoogle Scholar
  55. Kesavapany S, Pareek TK, Zheng YL, Amin N, Gutkind JS, Ma W, Kulkarni AB, Grant P, Pant HC. (2006/7) Neuronal nuclear organization is controlled by cyclin-dependent kinase 5 phosphorylation of Ras Guanine nucleotide releasing factor-1. Neurosignals. 15: 157–173.CrossRefGoogle Scholar
  56. Keshvara L, Magdaleno S, Benhayon D, Curran T. (2002) Cyclin-dependent kinase 5 phosphorylates disabled 1 independently of Reelin signaling. J. Neurosci. 22: 4869–4877.PubMedGoogle Scholar
  57. Kim Y, Sung JY, Ceglia I, Lee KW, Ahn JH, Halford JM, Kim AM, Kwak SP, Park JB, Ho Ryu S, Schenck A, Bardoni B, Scott JD, Nairn AC, Greengard P. (2006) Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442: 814–817.PubMedCrossRefGoogle Scholar
  58. Kino T, Ichijo T, Amin ND, Kesavapany S, Wang Y, Kim N, RaoS, Player A, Zheng Y, Garabedian MJ, Kawasaki E, Pant HC, Chrousos GP (2007) Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation: Clinical implications for the Nervous system response to glucocorticoids and stress. Mol. Endocrinology 21: 1552–1568.CrossRefGoogle Scholar
  59. Kwon YT, Gupta A, Zhou Y, Nikolic M, Tsai LH. (2000) Regulation of N-cadherin-mediated adhesion by the p35/Cdk5 kinase. Curr. Biol. 10: 363–372.PubMedCrossRefGoogle Scholar
  60. Lau KF, Howlett DR, Kesavapany S, Standen CL, Dingwall C, McLoughlin DM, Miller CC (2002) Cyclin-dependent kinase-5/p35 phosphorylates Presenilin 1 to regulate carboxy-terminal fragment stability. Mol. Cell. Neurosci. 20: 13–20.PubMedCrossRefGoogle Scholar
  61. Ledda F, Paratcha G, Ibanez CF. (2002) Target-derived GFRalpha1 as an attractive guidance signal for developing sensory and sympathetic axons via activation of Cdk5. Neuron 36: 387–401.PubMedCrossRefGoogle Scholar
  62. Ledee DR, Tripathi BK, Zelenka PS. (2007) The CDK5 activator, p39, binds specifically to myosin essential light chain. Biochem. Biophys. Res. Commun. 354: 1034–1039.PubMedCrossRefGoogle Scholar
  63. Lee SY, Wenk MR, Kim Y, Nairn AC, De Camilli P. (2004) Regulation of synaptojanin 1 by cyclin-dependent kinase 5 at synapses. Proc. Natl. Acad. Sci. U.S.A. 101: 546–551.PubMedCrossRefGoogle Scholar
  64. Lee SY, Voronov S, Letinic K, Nairn AC, Di Paolo G, De Camilli P. (2005) Regulation of the interaction between PIPKI gamma and talin by proline-directed protein kinases. J. Cell. Biol. 168: 789–799.PubMedCrossRefGoogle Scholar
  65. Lee JH, Kim HS, Lee SJ, Kim KT. (2007) Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death. J. Cell. Sci. 120: 2259–2271.PubMedCrossRefGoogle Scholar
  66. Li BS, Sun MK, Zhang L, Takahashi S, Ma W, Vinade L, Kulkarni AB, Brady RO, Pant HC. (2001) Regulation of NMDA receptors by cyclin-dependent kinase-5. Proc. Natl. Acad. Sci. U.S.A. 98: 12742–12747.PubMedCrossRefGoogle Scholar
  67. Li BS, Zhang L, Takahashi S, Ma W, Jaffe H, Kulkarni AB, Pant HC. (2002). Cyclin-dependent kinase 5 prevents neuronal apoptosis by negative regulation of c-Jun N-terminal kinase 3. EMBO J. 21: 324–333.PubMedCrossRefGoogle Scholar
  68. Li BS, Ma W, Jaffe H, Zheng Y, Takahashi S, Zhang L, Kulkarni AB, Pant HC. (2003) Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J. Biol. Chem. 278: 35702–35709.PubMedCrossRefGoogle Scholar
  69. Li C, Sasaki Y, Takei K, Yamamoto H, Shouji M, Sugiyama Y, Kawakami T, Nakamura F, Yagi T, Ohshima T, Goshima Y. (2004a) Correlation between semaphorin3A-induced facilitation of axonal transport and local activation of a translation initiation factor eukaryotic translation initiation factor 4E. J. Neurosci. 24: 6161–6170.CrossRefGoogle Scholar
  70. Li Z, David G, Hung KW, DePinho RA, Fu AK, Ip N.Y. (2004b) Cdk5/p35 phosphorylates mSds3 and regulates mSds3-mediated repression of transcription. J. Biol. Chem. 279: 54438–54444.CrossRefGoogle Scholar
  71. Li S, Tian X, Hartley DM, Feig LA. (2006) Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the induction of long-term potentiation and long-term depression. J. Neurosci. 26: 1721–1729.PubMedCrossRefGoogle Scholar
  72. Liang S, Wei FY, Wu YM, Tanabe K, Abe T, Oda Y, Yoshida Y, Yamada H, Matsui H, Tomizawa K, Takei K. (2007) Major Cdk5-dependent phosphorylation sites of amphiphysin 1 are implicated in the regulation of the membrane binding and endocytosis. J. Neurochem. (doi:10.1111/j.1471-4159.2007.04507.x)Google Scholar
  73. Lilien J, Balsamo J. (2005) The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin. Curr Opin Cell Biol. 17: 459–465.PubMedCrossRefGoogle Scholar
  74. Lilja L, Johansson JU, Gromada J, Mandic SA, Fried G, Berggren PO, Bark C. (2004) Cyclin-dependent kinase 5 associated with p39 promotes Munc18-1 phosphorylation and Ca(2+)-dependent exocytosis. J. Biol. Chem. 279: 29534–29541.PubMedCrossRefGoogle Scholar
  75. Lin W, Dominguez B, Yang J, Aryal P, Brandon EP, Gage FH, Lee KF. (2005) Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism. Neuron 46: 569–579.PubMedCrossRefGoogle Scholar
  76. Liu F, Ma XH, Ule J, Bibb JA, Nishi A, DeMaggio AJ, Yan Z, Nairn AC, Greengard P. (2001) Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors. Proc. Natl. Acad. Sci. U.S.A. 98: 11062–11068.PubMedCrossRefGoogle Scholar
  77. Liu F, Virshup DM, Nairn AC, Greengard P. (2002) Mechanism of regulation of casein kinase I activity by group I metabotropic glutamate receptors. J. Biol. Chem. 277: 45393–45399.PubMedCrossRefGoogle Scholar
  78. Liu F, Su Y, Li B, Zhou Y, Ryder J, Gonzalez-DeWhitt P, May PC, Ni B. (2003) Regulation of amyloid precursor protein (APP) phosphorylation and processing by p35/Cdk5 and p25/Cdk5. FEBS Lett. 547: 193–196.PubMedCrossRefGoogle Scholar
  79. Malenka RC, Bear MF. (2004) LTP and LTD: an embarrassment of riches. Neuron 44: 5–21.PubMedCrossRefGoogle Scholar
  80. Matsubara M, Kusubata M, Ishiguro K, Uchida T, Titani K, Taniguchi H. (1996) Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions. J. Biol. Chem. 271: 21108–21113.PubMedCrossRefGoogle Scholar
  81. Mizuno K, Plattner F, Giese KP. (2006) Expression of p25 impairs contextual learning but not latent inhibition in mice. Neuroreport. 17: 1903–1905.PubMedCrossRefGoogle Scholar
  82. Morabito MA, Sheng M, Tsai LH. (2004) Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J. Neurosci. 24: 865–876.PubMedCrossRefGoogle Scholar
  83. Morfini G, Szebenyi G, Brown H, Pant HC, Pigino G, DeBoer S, Beffert U, Brady ST. (2004) A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons. EMBO J. 23: 2235–2245.PubMedCrossRefGoogle Scholar
  84. Moy LY, Tsai LH. (2004) Cyclin-dependent kinase 5 phosphorylates serine 31 of tyrosine hydroxylase and regulates its stability. J. Biol. Chem. 279: 54487–54493.PubMedCrossRefGoogle Scholar
  85. Murase S, Mosser E, Schuman EM. (2002) Depolarization drives beta-Catenin into neuronal spines promoting changes in synaptic structure and function. Neuron 35: 91–105.PubMedCrossRefGoogle Scholar
  86. Negash S, Wang HS, Gao C, Ledee D, Zelenka P. (2002) Cdk5 regulates cell-matrix and cell-cell adhesion in lens epithelial cells. J. Cell. Sci. 115: 2109–2117.PubMedGoogle Scholar
  87. Nguyen C, Nishi A, Kansy JW, Fernandez J, Hayashi K, Gillardon F, Hemmings HC Jr, Nairn AC, Bibb JA. (2007) Regulation of protein phosphatase inhibitor-1 by cyclin-dependent kinase 5. J. Biol. Chem. 282: 16511–16520.PubMedCrossRefGoogle Scholar
  88. Nikolic M, Chou MM, Lu W, Mayer BJ, Tsai LH. (1998) The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature. 395: 194–198.PubMedCrossRefGoogle Scholar
  89. Nikonenko I, Jourdain P, Alberi S, Toni N, Muller D. (2002) Activity-induced changes of spine morphology. Hippocampus 12, 585–591.PubMedCrossRefGoogle Scholar
  90. Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P. (2000) Amplification of dopaminergic signaling by a positive feedback loop. Proc. Natl. Acad. Sci. U.S.A. 97: 12840–12845.PubMedCrossRefGoogle Scholar
  91. Norrholm SD, Bibb JA, Nestler EJ, Ouimet CC, Taylor JR, Greengard P. (2003) Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5. Neuroscience 116: 19–22.PubMedCrossRefGoogle Scholar
  92. O'Hare MJ, Kushwaha N, Zhang Y, Aleyasin H, Callaghan SM, Slack RS, Albert PR, Vincent I, Park D.S. (2005) Differential roles of nuclear and cytoplasmic cyclin-dependent kinase 5 in apoptotic and excitotoxic neuronal death. J. Neurosci. 25: 8954–8966.PubMedCrossRefGoogle Scholar
  93. Ohshima T, Ogura H, Tomizawa K et al. (2005) Impairment of hippocampal long-term depression and defective spatial learning and memory in p35 mice. J. Neurochem. 94: 917–925.PubMedCrossRefGoogle Scholar
  94. Ohshima T, Suzuki H, Morimura T, Ogawa M, Mikoshiba K (2007) Modulation of reelin signaling by cyclin-dependent kinase 5. Brain Res. 1140: 84–95.PubMedCrossRefGoogle Scholar
  95. Orellana DI, Quintanilla RA, Maccioni RB. (2007) Neuroprotective effect of TNFalpha against the beta-amyloid neurotoxicity mediated by CDK5 kinase. Biochim Biophys Acta. 1773: 254–263.PubMedCrossRefGoogle Scholar
  96. Paratcha G, Ibanez CF, Ledda F. (2006) GDNF is a chemoattractant factor for neuronal precursor cells in the rostral migratory stream. Mol Cell Neurosci. 31: 505–514.PubMedCrossRefGoogle Scholar
  97. Patel LS, Wenzel HJ, Schwartzkroin PA. (2004) Physiological and morphological characterization of dentate granule cells in the p35 knock-out mouse hippocampus: evidence for an epileptic circuit. J. Neurosci. 24: 9005–9014.PubMedCrossRefGoogle Scholar
  98. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402: 615–622.PubMedCrossRefGoogle Scholar
  99. Patzke H, Maddineni U, Ayala R, Morabito M, Volker J, Dikkes P, Ahlijanian MK, Tsai LH. (2003) Partial rescue of the p35–/– brain phenotype by low expression of a neuronal-specific enolase p25 transgene. J Neurosci 23: 2769–2778.PubMedGoogle Scholar
  100. Plattner F, Angelo M, Giese KP. (2006). The roles of Cdk5 and GSK3 in tau hyperphosphorylation. J. Biol. Chem. 281: 25457–25466.PubMedCrossRefGoogle Scholar
  101. Rashid T, Banerjee M, Nikolic M. (2001) Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology. J. Biol. Chem. 276: 49043–49052.PubMedCrossRefGoogle Scholar
  102. Ris L, Angelo M, Plattner F, Capron B, Errington ML, Bliss TV, Godaux E, Giese KP. (2005) Sexual dimorphisms in the effect of low-level p25 expression on synaptic plasticity and memory. Eur. J. Neurosci. 21: 3023–3033.CrossRefGoogle Scholar
  103. Roselli F, Tirard M, Lu J, Hutzler P, Lamberti P, Livrea P, Morabito M, Almeida OF. (2005) Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J. Neurosci. 25: 11061–11070.PubMedCrossRefGoogle Scholar
  104. Saito T, Onuki R, Fujita Y, Kusakawa G, Ishiguro K, Bibb JA, Kishimoto T, Hisanaga S. (2003) Developmental regulation of the proteolysis of the p35 cyclin-dependent kinase 5 activator by phosphorylation. J. Neurosci. 23: 1189–1197.PubMedGoogle Scholar
  105. Samuels BA, Hsueh YP, Shu T, Liang H, Tseng HC, Hong CJ, Su SC, Volker J, Neve RL, Yue DT, Tsai LH. (2007) Cdk5 Promotes Synaptogenesis by Regulating the Subcellular Distribution of the MAGUK Family Member CASK. Neuron 56: 823–837.PubMedCrossRefGoogle Scholar
  106. Sananbenesi F, Fischer A, Wang X, Schrick C, Neve R, Radulovic J, Tsai LH. (2007) A hippocampal Cdk5 pathway regulates extinction of contextual fear. Nat. Neurosci. 10: 1012–1019.PubMedCrossRefGoogle Scholar
  107. Sarker KP, Lee KY. (2004) L6 myoblast differentiation is modulated by Cdk5 via the PI3 K-AKT-p70S6 K signaling pathway. Oncogene 23: 6064–6070.PubMedCrossRefGoogle Scholar
  108. Sato Y, Taoka M, Sugiyama N, Kubo K, Fuchigami T, Asada A, Saito T, Nakajima K, Isobe T, Hisanaga S. (2007) Regulation of the interaction of Disabled-1 with CIN85 by phosphorylation with Cyclin-dependent kinase 5. Genes Cells. 12: 1315–1327.PubMedCrossRefGoogle Scholar
  109. Schuman EM, Murase S. (2003) Cadherins and synaptic plasticity: activity-dependent cyclin-dependent kinase 5 regulation of synaptic beta-catenin-cadherin interactions. Philos. Trans. R. Soc. Lond. B Biol. Sci. 358: 749–756.PubMedCrossRefGoogle Scholar
  110. Segal M. (2005) Dendritic spines and long-term plasticity. Nat. Rev. Neurosci. 6: 277–284.PubMedCrossRefGoogle Scholar
  111. Sengupta A, Novak M, Grundke-Iqbal I, Iqbal K. (2006) Regulation of phosphorylation of tau by cyclin-dependent kinase 5 and glycogen synthase kinase-3 at substrate level. FEBS Lett. 580: 5925–5933.PubMedCrossRefGoogle Scholar
  112. Sharma P, Veeranna, Sharma M, Amin ND, Sihag RK, Grant P, Ahn N, Kulkarni AB, Pant HC. (2002) Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway. J. Biol. Chem. 277: 528–534.PubMedCrossRefGoogle Scholar
  113. Sharma M, Hanchate NK, Tyagi RK, Sharma P. (2007) Cyclin dependent kinase 5 (Cdk5) mediated inhibition of the MAP kinase pathway results in CREB down regulation and apoptosis in PC12 cells. Biochem. Biophys. Res. Commun. 358: 379–384.PubMedCrossRefGoogle Scholar
  114. Takahashi S, Ohshima T, Cho A, et al. (2005) Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling. Proc. Natl. Acad. Sci. U.S.A. 102: 1737–1742.PubMedCrossRefGoogle Scholar
  115. Tan TC, Valova VA, Malladi CS, et al. (2003) Cdk5 is essential for synaptic vesicle endocytosis. Nat. Cell. Biol. 5: 701–710.PubMedCrossRefGoogle Scholar
  116. Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ. (1999). Genetic enhancement of learning and memory in mice. Nature 401: 63–69.PubMedCrossRefGoogle Scholar
  117. Taniguchi M, Taoka M, Itakura M, Asada A, Saito T, Kinoshita M, Takahashi M, Isobe T, Hisanaga S. (2007) Phosphorylation of adult type Sept5 (CDCrel-1) by cyclin-dependent kinase 5 inhibits interaction with syntaxin-1. J. Biol. Chem. 282: 7869–7876.PubMedCrossRefGoogle Scholar
  118. Tomizawa K, Ohta J, Matsushita M, Moriwaki A, Li ST, Takei K, Matsui H. (2002) Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity. J. Neurosci. 22: 2590–2597.PubMedGoogle Scholar
  119. Tomizawa K, Sunada S, Lu YF, et al. (2003) Cophosphorylation of amphiphysin I and dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles. J. Cell. Biol. 163: 813–824.PubMedCrossRefGoogle Scholar
  120. Venturin M, Moncini S, Villa V, Russo S, Bonati MT, Larizza L, Riva P. (2006) Mutations and novel polymorphisms in coding regions and UTRs of CDK5R1 and OMG genes in patients with non-syndromic mental retardation. Neurogenetics 7: 59–66.PubMedCrossRefGoogle Scholar
  121. Wang J, Liu S, Fu Y, Wang JH, Lu Y. (2003) Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors. Nat. Neurosci. 6: 1039–1047.PubMedCrossRefGoogle Scholar
  122. Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R. (2004) Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J. Neurosci. 24: 3370–3378.PubMedCrossRefGoogle Scholar
  123. Wei FY, Nagashima K, Ohshima T et al. (2005a) Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nat. Med. 11: 1104–1108.CrossRefGoogle Scholar
  124. Wei FY, Tomizawa K, Ohshima T, et al. (2005b). Control of cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability. J. Neurochem. 93: 502–512.CrossRefGoogle Scholar
  125. Wenzel HJ, Robbins CA, Tsai LH, Schwartzkroin PA. (2001) Abnormal morphological and functional organization of the hippocampus in a p35 mutant model of cortical dysplasia associated with spontaneous seizures. J Neurosci 21: 983–998.PubMedGoogle Scholar
  126. Xin X, Ferraro F, Back N, Eipper BA, Mains RE. (2004) Cdk5 and Trio modulate endocrine cell exocytosis. J. Cell. Sci. 117: 4739–4748.PubMedCrossRefGoogle Scholar
  127. Yan Z, Chi P, Bibb JA, Ryan TA, Greengard P. (2002) Roscovitine: a novel regulator of P/Q-type calcium channels and transmitter release in central neurons. J. Physiol. 540: 761–770.PubMedCrossRefGoogle Scholar
  128. Yamashita N, Morita A, Uchida Y, Nakamura F, Usui H, Ohshima T, Taniguchi M, Honnorat J, Thomasset N, Takei K, Takahashi T, Kolattukudy P, Goshima Y. (2007) Regulation of spine development by semaphorin3A through cyclin-dependent kinase 5 phosphorylation of collapsin response mediator protein 1. J. Neurosci. 27: 12546–12554.PubMedCrossRefGoogle Scholar
  129. Zhang J, Krishnamurthy PK, Johnson GV. (2002) Cdk5 phosphorylates p53 and regulates its activity. J. Neurochem. 81: 307–313.PubMedCrossRefGoogle Scholar
  130. Zhen X, Goswami S, Abdali SA, Gil M, Bakshi K, Friedman E. (2004) Regulation of cyclin-dependent kinase 5 and calcium/calmodulin-dependent protein kinase II by phosphatidylinositol-linked dopamine receptor in rat brain Mol. Pharmacol. 66: 1500–1507.Google Scholar
  131. Zheng YL, Li BS, Kanungo J, Kesavapany S, Amin N, Grant P, Pant HC. (2007) Cdk5 Modulation of mitogen-activated protein kinase signaling regulates neuronal survival. Mol. Biol. Cell. 18: 404–413.PubMedCrossRefGoogle Scholar
  132. Zucker RS, Regehr WG. (2002) Short-term synaptic plasticity. Annu. Rev. Physiol. 64: 355–405.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Florian Plattner
    • 1
  • K. Peter Giese
  • Marco Angelo
    • 1
  1. 1.Institute of NeurologyUniversity College LondonUK

Personalised recommendations