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CDK5 downregulation enhances synaptic plasticity

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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.

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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

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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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Authors and Affiliations

  1. Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, Faculty of Medicine, SIU, University of Antioquia, Calle 62 # 52-59, Torre 1, Piso 4, Laboratorio 412, Medellín, Colombia

    Rafael Andrés Posada-Duque & Gloria Patricia Cardona-Gómez

  2. Laboratory for Scientific Image Analysis (SCIAN-Lab), Center for Medical Informatics and Telemedicine (CIMT), Biomedical Neuroscience Institute BNI, ICBM, Universidad de Chile, Santiago, Chile

    Omar Ramirez & Steffen Härtel

  3. Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Centro de Envejecimiento y Regeneración, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile

    Nibaldo C. Inestrosa

  4. Laboratory of Cell and Neuronal Dynamics, Department of Biology, Faculty of Sciences, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago, Chile

    Felipe Bodaleo & Christian González-Billault

  5. Geroscience Center for Brain Health and Metabolism, Santiago, Chile

    Felipe Bodaleo & Christian González-Billault

  6. Solomon H. Snyder Department of Neuroscience, Zanvyl-Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, USA

    Alfredo Kirkwood

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  1. Rafael Andrés Posada-Duque
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  3. Steffen Härtel
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  4. Nibaldo C. Inestrosa
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  5. Felipe Bodaleo
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  6. Christian González-Billault
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  7. Alfredo Kirkwood
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  8. Gloria Patricia Cardona-Gómez
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Corresponding author

Correspondence to Gloria Patricia Cardona-Gómez.

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This work presents new findings that CDK5 RNAi induces neuroplastic changes in mature neurons. Interestingly, we show that CDK5 downregulation induces dendritic protrusion morphogenesis and increases LTP in both normal and dysfunctional synapses. CDK5 RNAi neuroplasticity was confirmed by calcium in neurites and enhancement of BDNF/CREB activation.

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Posada-Duque, R.A., Ramirez, O., Härtel, S. et al. CDK5 downregulation enhances synaptic plasticity. Cell. Mol. Life Sci. 74, 153–172 (2017). https://doi.org/10.1007/s00018-016-2333-8

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  • DOI: https://doi.org/10.1007/s00018-016-2333-8

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