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Cellular and Molecular Life Sciences

, Volume 74, Issue 1, pp 153–172 | Cite as

CDK5 downregulation enhances synaptic plasticity

  • Rafael Andrés Posada-Duque
  • Omar Ramirez
  • Steffen Härtel
  • Nibaldo C. Inestrosa
  • Felipe Bodaleo
  • Christian González-Billault
  • Alfredo Kirkwood
  • Gloria Patricia Cardona-Gómez
Original Article

Abstract

CDK5 is a serine/threonine kinase that is involved in the normal function of the adult brain and plays a role in neurotransmission and synaptic plasticity. However, its over-regulation has been associated with Tau hyperphosphorylation and cognitive deficits. Our previous studies have demonstrated that CDK5 targeting using shRNA-miR provides neuroprotection and prevents cognitive deficits. Dendritic spine morphogenesis and forms of long-term synaptic plasticity—such as long-term potentiation (LTP)—have been proposed as essential processes of neuroplasticity. However, whether CDK5 participates in these processes remains controversial and depends on the experimental model. Using wild-type mice that received injections of CDK5 shRNA-miR in CA1 showed an increased LTP and recovered the PPF in deficient LTP of APPswe/PS1Δ9 transgenic mice. On mature hippocampal neurons CDK5, shRNA-miR for 12 days induced increased dendritic protrusion morphogenesis, which was dependent on Rac activity. In addition, silencing of CDK5 increased BDNF expression, temporarily increased phosphorylation of CaMKII, ERK, and CREB; and facilitated calcium signaling in neurites. Together, our data suggest that CDK5 downregulation induces synaptic plasticity in mature neurons involving Ca2+ signaling and BDNF/CREB activation.

Keywords

CDK5 RNAi Dendritic protrusion morphogenesis BDNF/CREB Calcium Synaptic plasticity LTP 

Abbreviations

CDK5

Cyclin-dependent kinase 5

Glu

Glutamate

AD

Alzheimer’s disease

DIV

Day in vitro

MAP-2

Microtubule-associated protein-2

ROCK

Rho kinase

SDS-PAGE

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

DTT

Dithiothreitol

G-LISA

GTP enzyme-linked immunosorbent assay

IFU

Infectious units of virus

PSD95

Postsynaptic density-95

NMDAR

NMDA receptor

3xTg-AD

Triple transgenic Alzheimer’s disease mice

AAV

Adeno-associated virus

shRNA-miR

Short hairpin RNA in a microRNA backbone

PAK

p21-activated kinase

Scr

Scrambled

Notes

Acknowledgments

The authors thank American Journal Experts for editing the English language in this manuscript. This research was supported by a grant from the Colciencias, projects # 111545921503 and #111554531400 (GPC-G), Mobility’s Project Colombia-Chile 576-2011, and the PROLAB Collaboration in Latin America/IBRO (CG-B and GPC-G). In addition, the Fogarty International Center and the NIA of NIH under Award Number RO1-AG029802-01 supported this research (GPC-G). R.A.P.-D. was sponsored by ENLAZA mundos fellowship. F.B. and C.G.-B. were supported by FONDAP Grant 15150012, and OR and SH were supported by FONDECYT 1151029, CONICYT PIA ACT1402, DAAD and ICM P09-015-F (Chile). The authors would like to thank the Advanced Microscopy Unit and Viral Vector and Gene Therapy Cores of the Group of Neuroscience of the University of Antioquia. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Rafael Andrés Posada-Duque
    • 1
  • Omar Ramirez
    • 2
  • Steffen Härtel
    • 2
  • Nibaldo C. Inestrosa
    • 3
  • Felipe Bodaleo
    • 4
    • 5
  • Christian González-Billault
    • 4
    • 5
  • Alfredo Kirkwood
    • 6
  • Gloria Patricia Cardona-Gómez
    • 1
  1. 1.Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, Faculty of Medicine, SIUUniversity of AntioquiaMedellínColombia
  2. 2.Laboratory for Scientific Image Analysis (SCIAN-Lab), Center for Medical Informatics and Telemedicine (CIMT), Biomedical Neuroscience Institute BNI, ICBMUniversidad de ChileSantiagoChile
  3. 3.Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Centro de Envejecimiento y RegeneraciónPontificia Universidad Católica de ChileSantiagoChile
  4. 4.Laboratory of Cell and Neuronal Dynamics, Department of Biology, Faculty of SciencesUniversidad de ChileSantiagoChile
  5. 5.Geroscience Center for Brain Health and MetabolismSantiagoChile
  6. 6.Solomon H. Snyder Department of NeuroscienceZanvyl-Krieger Mind/Brain Institute, Johns Hopkins UniversityBaltimoreUSA

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