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Cdk5 Contributes to Huntington’s Disease Learning and Memory Deficits via Modulation of Brain Region-Specific Substrates

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Abstract

Cognitive deficits are a major hallmark of Huntington’s disease (HD) with a great impact on the quality of patient’s life. Gaining a better understanding of the molecular mechanisms underlying learning and memory impairments in HD is, therefore, of critical importance. Cdk5 is a proline-directed Ser/Thr kinase involved in the regulation of synaptic plasticity and memory processes that has been associated with several neurodegenerative disorders. In this study, we aim to investigate the role of Cdk5 in learning and memory impairments in HD using a novel animal model that expresses mutant huntingtin (mHtt) and has genetically reduced Cdk5 levels. Genetic reduction of Cdk5 in mHtt knock-in mice attenuated both corticostriatal learning deficits as well as hippocampal-dependent memory decline. Moreover, the molecular mechanisms by which Cdk5 counteracts the mHtt-induced learning and memory impairments appeared to be differentially regulated in a brain region-specific manner. While the corticostriatal learning deficits are attenuated through compensatory regulation of NR2B surface levels, the rescue of hippocampal-dependent memory was likely due to restoration of hippocampal dendritic spine density along with an increase in Rac1 activity. This work identifies Cdk5 as a critical contributor to mHtt-induced learning and memory deficits. Furthermore, we show that the Cdk5 downstream targets involved in memory and learning decline differ depending on the brain region analyzed suggesting that distinct Cdk5 effectors could be involved in cognitive impairments in HD.

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References

  1. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983

    Article  Google Scholar 

  2. Graveland GA, Williams RS, DiFiglia M (1985) Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science 227(4688):770–773. https://doi.org/10.1126/science.3155875

    Article  PubMed  CAS  Google Scholar 

  3. Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB (1988) Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci U S A 85(15):5733–5737. https://doi.org/10.1073/pnas.85.15.5733

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Cepeda C, Wu N, André VM et al (2007) The corticostriatal pathway in Huntington’s disease. Prog Neurobiol 81(5-6):253–271. https://doi.org/10.1016/j.pneurobio.2006.11.001

    Article  PubMed  CAS  Google Scholar 

  5. Ransome MI, Renoir T, Hannan AJ (2012) Hippocampal neurogenesis, cognitive deficits and affective disorder in Huntington’s disease. Neural Plast 2012:1–7. https://doi.org/10.1155/2012/874387

    Article  Google Scholar 

  6. Lawrence AD, Hodges JR, Rosser AE, Kershaw A, ffrench-Constant C, Rubinsztein DC, Robbins TW, Sahakian BJ (1998) Evidence for specific cognitive deficits in preclinical Huntington’s disease. Brain 121(7):1329–1341. https://doi.org/10.1093/brain/121.7.1329

    Article  PubMed  Google Scholar 

  7. Duff K, Paulsen J, Mills J, Beglinger LJ, Moser DJ, Smith MM, Langbehn D, Stout J et al (2010) Mild cognitive impairment in prediagnosed Huntington’s disease. Neurology 75(6):500–507. https://doi.org/10.1212/WNL.0b013e3181eccfa2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Gray MA, Egan GF, Ando A, Churchyard A, Chua P, Stout JC, Georgiou-Karistianis N (2013) Prefrontal activity in Huntington’s disease reflects cognitive and neuropsychiatric disturbances: the IMAGE-HD study. Exp Neurol 239:218–228. https://doi.org/10.1016/j.expneurol.2012.10.020

    Article  PubMed  CAS  Google Scholar 

  9. Lemiere J, Decruyenaere M, Evers-Kiebooms G, Vandenbussche E, Dom R (2004) Cognitive changes in patients with Huntington’s disease (HD) and asymptomatic carriers of the HD mutation. J Neurol 251(8):935–942. https://doi.org/10.1007/s00415-004-0461-9

    Article  PubMed  CAS  Google Scholar 

  10. Smith R, Brundin P, Li J (2005) Synaptic dysfunction in Huntington’s disease : a new perspective. Cell Mol Life Sci 62(17):1901–1912. https://doi.org/10.1007/s00018-005-5084-5

    Article  PubMed  CAS  Google Scholar 

  11. Nithianantharajah J, Hannan AJ (2013) Dysregulation of synaptic proteins, dendritic spine abnormalities and pathological plasticity of synapses as experience-dependent mediators of cognitive and psychiatric symptoms in Huntington’s disease. Neuroscience 251:66–74. https://doi.org/10.1016/j.neuroscience.2012.05.043

    Article  PubMed  CAS  Google Scholar 

  12. Raymond LA (2016) Striatal synaptic dysfunction and altered calcium regulation in Huntington disease. Biochem Biophys Res Commun 483(4):1051–1062. https://doi.org/10.1016/j.bbrc.2016.07.058

    Article  PubMed  CAS  Google Scholar 

  13. Puigdellívol M, Saavedra A, Pérez-Navarro E (2016) Cognitive dysfunction in Huntington’s disease: mechanisms and therapeutic strategies beyond BDNF. Brain Pathol 1(6):1–59. https://doi.org/10.1111/bpa.12432

    Article  CAS  Google Scholar 

  14. Li JY, Plomann M, Brundin P (2003) Huntington’s disease: a synaptopathy? Trends Mol Med 9(10):414–420. https://doi.org/10.1016/j.molmed.2003.08.006

    Article  PubMed  CAS  Google Scholar 

  15. Rozas JL, Gómez-Sánchez L, Tomás-Zapico C, Lucas JJ, Fernández-Chacón R (2010) Presynaptic dysfunction in Huntington’s disease. Biochem Soc Trans 38(2):488–492. https://doi.org/10.1042/BST0380488

    Article  PubMed  CAS  Google Scholar 

  16. Milnerwood AJ, Raymond LA (2007) Corticostriatal synaptic function in mouse models of Huntington’s disease: early effects of huntingtin repeat length and protein load. J Physiol 585(3):817–831. https://doi.org/10.1113/jphysiol.2007.142448

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Raymond LA, André VM, Cepeda C, Gladding CM, Milnerwood AJ, Levine MS (2011) Pathophysiology of Huntington’s disease: time-dependent alterations in synaptic and receptor function. Neuroscience 198:252–273. https://doi.org/10.1016/j.neuroscience.2011.08.052

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Wang N, Gray M, X-H L, Cantle JP, Holley SM, Greiner E, Gu X, Shirasaki D et al (2014) Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington’s disease. Nat Med 20(5):536–541. https://doi.org/10.1038/nm.3514

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Spires TL, Grote HE, Garry S, Cordery PM, Van Dellen A, Blakemore C, Hannan AJ (2004) Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington’s disease transgenic mice. Neuroscience. https://doi.org/10.1111/j.1460-9568.2004.03374.x

  20. Murmu R, Li W, Holtmaat A, Li J (2013) Dendritic spine instability leads to progressive neocortical spine loss in a mouse model of Huntington’s disease. J Neurosci 33(32):12997–13009. https://doi.org/10.1523/JNEUROSCI.5284-12.2013

    Article  PubMed  CAS  Google Scholar 

  21. Brito V, Giralt A, Enriquez-Barreto L, Puigdellívol M, Suelves N, Zamora-Moratalla A, Ballesteros JJ, Martín ED et al (2014) Neurotrophin receptor p75 NTR mediates Huntington’s disease—associated synaptic and memory dysfunction. J Clin Invest 124(10):4411–4428. https://doi.org/10.1172/JCI74809.long-term

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Puigdellívol M, Cherubini M, Brito V, Giralt A, Suelves N, Ballesteros J, Zamora-Moratalla A, Martín ED et al (2015) A role for Kalirin-7 in corticostriatal synaptic dysfunction in Huntington’s disease. Hum Mol Genet 24(25):7265–7285. https://doi.org/10.1093/hmg/ddv426

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Herms J, Dorostkar MM (2016) Dendritic spine pathology in neurodegenerative diseases. Annu Rev Pathol 11(1):221–250. https://doi.org/10.1146/annurev-pathol-012615-044216

    Article  PubMed  CAS  Google Scholar 

  24. Tsai LH, Delalle I, Caviness VS, Chae T, Harlow E (1994) P35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371(6496):419–423. https://doi.org/10.1038/371419a0

    Article  PubMed  CAS  Google Scholar 

  25. Dhavan R, Tsai LH (2001) A decade of CDK5. Nat Rev Mol Cell Biol 2(10):749–759. https://doi.org/10.1038/35096019

    Article  PubMed  CAS  Google Scholar 

  26. Angelo M, Plattner F, Giese KP (2006) Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. J Neurochem 99(2):353–370. https://doi.org/10.1111/j.1471-4159.2006.04040.x

    Article  PubMed  CAS  Google Scholar 

  27. Lai KO, Ip NY (2009) Recent advances in understanding the roles of Cdk5 in synaptic plasticity. Biochim Biophys Acta Mol Basis Dis 1792(8):741–745. https://doi.org/10.1016/j.bbadis.2009.05.001

    Article  CAS  Google Scholar 

  28. McLinden KA, Trunova S, Giniger E (2012) At the fulcrum in health and disease: Cdk5 and the balancing acts of neuronal structure and physiology. Brain Disord Ther 1(s1):1–11. https://doi.org/10.4172/2168-975X.S1-001

    Article  Google Scholar 

  29. Li BS, Sun MK, Zhang L, Takahashi S, Ma W, Vinade L, Kulkarni AB, Brady RO et al (2001) Regulation of NMDA receptors by cyclin-dependent kinase-5. Proc Natl Acad Sci U S A 98(22):12742–12747. https://doi.org/10.1073/pnas.211428098

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM et al (2007) Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci 10(7):880–886. https://doi.org/10.1038/nn1914

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Plattner F, Hernández A, Kistler TM, Pozo K, Zhong P, Yuen EY, Tan C, Hawasli AH et al (2014) Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron 81(5):1070–1083. https://doi.org/10.1016/j.neuron.2014.01.022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Kim Y, Sung JY, Ceglia I, Lee KW, Ahn JH, Halford JM, Kim AM, Kwak SP et al (2006) Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442(7104):814–817. https://doi.org/10.1038/nature04976

    Article  PubMed  CAS  Google Scholar 

  33. Fu W-Y, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH et al (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 10(1):67–76. https://doi.org/10.1038/nn1811

    Article  PubMed  CAS  Google Scholar 

  34. Xin X, Wang Y, Ma X, Rompolas P, Keutmann HT, Mains RE, Eipper BA (2008) Regulation of Kalirin by Cdk5. J Cell Sci 121(15):2601–2611. https://doi.org/10.1242/jcs.016089

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Lai K-O, Liang Z, Fei E, Huang H, Ip NY (2015) Cdk5-dependent phosphorylation of p70 ribosomal S6 kinase (S6K) is required for dendritic spine morphogenesis. J Biol Chem 290(23):14637–14646. https://doi.org/10.1074/jbc.M114.627117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Alexander K, Yang H-S, Hinds PW (2004) Cellular senescence requires CDK5 repression of Rac1 activity. Mol Cell Biol 24(7):2808–2819. https://doi.org/10.1128/MCB.24.7.2808

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Posada-Duque RA, López-Tobón A, Piedrahita D, González-Billault C, Cardona-Gomez GP (2015) p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing. J Neurochem 134(2):1–17. https://doi.org/10.1111/jnc.13127

    Article  CAS  Google Scholar 

  38. Cheung ZH, Ip NY (2012) Cdk5: a multifaceted kinase in neurodegenerative diseases. Trends Cell Biol 22(3):169–175. https://doi.org/10.1016/j.tcb.2011.11.003

    Article  PubMed  CAS  Google Scholar 

  39. SC S, Tsai L-H (2011) Cyclin-dependent kinases in brain development and disease. Annu Rev Cell Dev Biol 27(1):465–491. https://doi.org/10.1146/annurev-cellbio-092910-154023

    Article  CAS  Google Scholar 

  40. Lopes JP, Agostinho P (2011) Cdk5: multitasking between physiological and pathological conditions. Prog Neurobiol 94(1):49–63. https://doi.org/10.1016/j.pneurobio.2011.03.006

    Article  PubMed  CAS  Google Scholar 

  41. Paoletti P, Vila I, Rifé M, Lizcano JM, Alberch J, Ginés A (2008) Dopaminergic and glutamatergic signaling crosstalk in Huntington’s disease neurodegeneration: the role of p25/cyclin-dependent kinase 5. J Neurosci 28(40):10090–10101. https://doi.org/10.1523/JNEUROSCI.3237-08.2008

    Article  PubMed  CAS  Google Scholar 

  42. Cherubini M, Puigdellívol M, Alberch J, Ginés S (2015) Cdk5-mediated mitochondrial fission: a key player in dopaminergic toxicity in Huntington’s disease. Biochim Biophys Acta Mol Basis Dis 1852(10):2145–2160. https://doi.org/10.1016/j.bbadis.2015.06.025

    Article  CAS  Google Scholar 

  43. Giralt A, Puigdellívol M, Carretón O, Paoletti P, Valero J, Parra-Damas A, Saura CA, Alberch J et al (2012) Long-term memory deficits in Huntington’s disease are associated with reduced CBP histone acetylase activity. Hum Mol Genet 21(6):1203–1216. https://doi.org/10.1093/hmg/ddr552

    Article  PubMed  CAS  Google Scholar 

  44. Gabriel LR, Wu S, Melikian HE (2014) Brain slice biotinylation: an ex vivo approach to measure region-specific plasma membrane protein trafficking in adult neurons. J Vis Exp 1506(86):1–6. https://doi.org/10.3791/51240

    Article  CAS  Google Scholar 

  45. Kimura T, Ishiguro K, Hisanaga S-I (2014) Physiological and pathological phosphorylation of tau by Cdk5. Front Mol Neurosci 7:65. https://doi.org/10.3389/fnmol.2014.00065

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Barnett DGS, Bibb JA (2011) The role of Cdk5 in cognition and neuropsychiatric and neurological pathology. Brain Res Bull 85(1–2):9–13. https://doi.org/10.1016/j.brainresbull.2010.11.016

    Article  PubMed  CAS  Google Scholar 

  47. Hawasli AH, Bibb JA (2007) Alternative roles for Cdk5 in learning and synaptic plasticity. Biotechnol J 2(8):941–948. https://doi.org/10.1002/biot.200700093

    Article  PubMed  CAS  Google Scholar 

  48. Izquierdo I (1991) Role of NMDA receptors in memory. Trends Pharmacol Sci 12(4):128–129. https://doi.org/10.1016/0165-6147(91)90527-Y

    Article  PubMed  CAS  Google Scholar 

  49. 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(6748):63–69. https://doi.org/10.1038/43432

    Article  PubMed  CAS  Google Scholar 

  50. Lau CG, Zukin RS (2007) NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8(6):413–426. https://doi.org/10.1038/nrn2153

    Article  PubMed  CAS  Google Scholar 

  51. 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(10):1039–1047. https://doi.org/10.1038/nn1119

    Article  PubMed  CAS  Google Scholar 

  52. Lu W, Ai H, Peng L, Wang JJ, Zhang B, Liu X, Luo JH (2015) A novel phosphorylation site of N-methyl-d-aspartate receptor GluN2B at S1284 is regulated by Cdk5 in neuronal ischemia. Exp Neurol 271:251–258. https://doi.org/10.1016/j.expneurol.2015.06.016

    Article  PubMed  CAS  Google Scholar 

  53. Zhang S, Edelmann L, Liu J, Crandall JE, Morabito MA (2008) Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors. J Neurosci 28(2):415–424. https://doi.org/10.1523/JNEUROSCI.1900-07.2008

    Article  PubMed  CAS  Google Scholar 

  54. Roskoski R (2005) Src kinase regulation by phosphorylation and dephosphorylation. Biochem Biophys Res Commun 331(1):1–14. https://doi.org/10.1016/j.bbrc.2005.03.012

    Article  PubMed  CAS  Google Scholar 

  55. 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(8):1012–1019. https://doi.org/10.1038/nn1943

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Guan JS, Su SC, Gao J, Joseph N, Xie Z, Zhou Y, Durak O, Zhang L et al (2011) Cdk5 is required for memory function and hippocampal plasticity via the camp signaling pathway. PLoS One 6(9):e25735. https://doi.org/10.1371/journal.pone.0025735

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Tashiro A, Minden A, Yuste R (2000) Regulation of dendritic spine morphology by the Rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb Cortex 10(10):927–938. https://doi.org/10.1093/cercor/10.10.927

    Article  PubMed  CAS  Google Scholar 

  58. Cheung ZH, AKY F, Ip NY (2006) Synaptic roles of Cdk5: implications in higher cognitive functions and neurodegenerative diseases. Neuron 50(1):13–18. https://doi.org/10.1016/j.neuron.2006.02.024

    Article  PubMed  CAS  Google Scholar 

  59. Park KHJ, Lu G, Fan J, Raymond LA, Leavitt BR (2012) Decreasing levels of the cdk5 activators, p25 and p35, reduces excitotoxicity in striatal neurons. Mol Med 1:97–104. https://doi.org/10.3233/JHD-2012-129000

    Article  Google Scholar 

  60. Bowles KR, Jones L (2014) Kinase Signalling in Huntington’s disease. J Huntingtons Dis 3(2):89–123. https://doi.org/10.3233/JHD-140106

    Article  PubMed  CAS  Google Scholar 

  61. Binukumar BK, Shukla V, Amin ND, Grant P, Bhaskar M, Skuntz S, Steiner J, Pant HC (2015) Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson’s disease. Mol Biol Cell 26(24):4478–4491. https://doi.org/10.1091/mbc.E15-06-0415

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Gutiérrez-Vargas JA, Múnera A, Cardona-Gómez GP (2015) CDK5 knockdown prevents hippocampal degeneration and cognitive dysfunction produced by cerebral ischemia. J Cereb Blood Flow Metab 1115545314(12):1–13. https://doi.org/10.1038/jcbfm.2015.150

    Article  CAS  Google Scholar 

  63. Luthi-Carter R, Apostol BL, Dunah AW, DeJohn MM, Farrell LA, Bates GP, Young AB, Standaert DG et al (2003) Complex alteration of NMDA receptors in transgenic Huntington’s disease mouse brain: analysis of mRNA and protein expression, plasma membrane association, interacting proteins, and phosphorylation. Neurobiol Dis 14(3):624–636. https://doi.org/10.1016/j.nbd.2003.08.024

    Article  PubMed  CAS  Google Scholar 

  64. Fan MMY, Fernandes HB, Zhang LYJ, Hayden MR, Raymond LA (2007) Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington’s disease. J Neurosci 27(14):3768–3779. https://doi.org/10.1523/JNEUROSCI.4356-06.2007

    Article  PubMed  CAS  Google Scholar 

  65. Luo S, Vacher C, Davies JE, Rubinsztein DC (2005) Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J Cell Biol 169(4):647–656. https://doi.org/10.1083/jcb.200412071

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Kaminosono S, Saito T, Oyama F, Ohshima T, Asada A, Nagai Y, Nukina N, Hisanaga S (2008) Suppression of mutant huntingtin aggregate formation by cdk5/p35 through the effect on microtubule stability. J Neurosci 28(35):8747–8755. https://doi.org/10.1523/JNEUROSCI.0973-08.2008

    Article  PubMed  CAS  Google Scholar 

  67. Anne SL, Saudou F, Humbert S (2007) Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons. J Neurosci 27(27):7318–7328. https://doi.org/10.1523/JNEUROSCI.1831-07.2007

    Article  PubMed  CAS  Google Scholar 

  68. Tashiro A, Yuste R (2004) Regulation of dendritic spine motility and stability by Rac1 and Rho kinase: evidence for two forms of spine motility. Mol Cell Neurosci 26(3):429–440. https://doi.org/10.1016/j.mcn.2004.04.001

    Article  PubMed  CAS  Google Scholar 

  69. Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21(1):247–269. https://doi.org/10.1146/annurev.cellbio.21.020604.150721

    Article  PubMed  CAS  Google Scholar 

  70. Tada T, Sheng M (2006) Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol 16(1):95–101. https://doi.org/10.1016/j.conb.2005.12.001

    Article  PubMed  CAS  Google Scholar 

  71. Posada-Duque RA, Palacio-Castañeda V, Cardona-Gómez GP (2015) CDK5 knockdown in astrocytes provide neuroprotection as a trophic source via Rac1. Mol Cell Neurosci 68:151–166. https://doi.org/10.1016/j.mcn.2015.07.001

    Article  PubMed  CAS  Google Scholar 

  72. Posada-Duque RA, Ramirez O, Härtel S, Inestrosa NC, Bodaleo F, González-Billault C, Kirkwood A, Cardona-Gómez GP (2016) CDK5 downregulation enhances synaptic plasticity. Cell Mol Life Sci 74(1):1–20. https://doi.org/10.1007/s00018-016-2333-8

    Article  CAS  Google Scholar 

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Acknowledgments

We are very grateful to Ana Lopez and Maria Teresa Muñoz for technical assistance, Dr. Teresa Rodrigo and the staff of the animal care facility (Facultat de Psicologia Universitat de Barcelona), and Dr. Maria Calvo, Anna Bosch, and Elisenda Coll from the Advanced Optical Microscopy Unit from Scientific and Technological Centers from the University of Barcelona for their support and advice with confocal technique. We thank Dr. Carles A. Saura for providing the Cre recombinase mice. We thank Dr. Paul Greengard for providing the Cdk5 flox/flox mice. We thank the members of our laboratory for helpful discussion.

Funding

This work was supported by Ministerio de Economía y Competitividad (SAF-2014-57160R to J.A. and SAF2015-67474-R;MINECO/FEDER to S.G.) and Centro de Investigaciones Biomédicas en Red sobre Enfermedades Neurodegenerativas (CIBERNED).

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Authors and Affiliations

  1. Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain

    Elena Alvarez-Periel, Mar Puigdellívol, Verónica Brito, Jordi Alberch & Silvia Ginés

  2. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Elena Alvarez-Periel, Mar Puigdellívol, Verónica Brito, Jordi Alberch & Silvia Ginés

  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Elena Alvarez-Periel, Mar Puigdellívol, Verónica Brito, Jordi Alberch & Silvia Ginés

  4. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Florian Plattner

  5. Departments of Surgery, Neurobiology, and Neurology, UAB Comprehensive Cancer Center, The University of Alabama at Birmingham Medical Center, Birmingham, AL, USA

    James A. Bibb

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  1. Elena Alvarez-Periel
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  2. Mar Puigdellívol
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  5. James A. Bibb
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  7. Silvia Ginés
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Correspondence to Silvia Ginés.

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All procedures were performed in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the local animal care committee of the Universitat de Barcelona (76/15) and Generalitat de Catalunya (00/1094), in accordance with the Directive 2010/63/EU of the European Commission.

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The authors declare that they have no competing interests.

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The authors wish it to be known that, in their opinion, Elena Alvarez-Periel and Mar Puigdellívol should be regarded as joint first authors.

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Alvarez-Periel, E., Puigdellívol, M., Brito, V. et al. Cdk5 Contributes to Huntington’s Disease Learning and Memory Deficits via Modulation of Brain Region-Specific Substrates. Mol Neurobiol 55, 6250–6268 (2018). https://doi.org/10.1007/s12035-017-0828-4

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