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Role of Cdk5 in Kalirin7-Mediated Formation of Dendritic Spines

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Abstract

A majority of excitatory synapses in the brain are localized on the dendritic spines. Alterations of spine density and morphology are associated with many neurological diseases. Understanding the molecular mechanisms underlying spine formation is important for understanding these diseases. Kalirin7 (Kal-7) is localized to the postsynaptic side of excitatory synapses in the neurons. Overexpression of Kal-7 causes an increase in spine density whereas knockdown expression of endogenous Kal-7 results in a decrease in spine density in primary cultured cortical neurons. However, the mechanisms underlying Kal-7-mediated spine formation are not entirely clear. Cyclin-dependent kinase 5 (Cdk5) plays a vital role in the formation of spines and synaptic plasticity. Kal-7 is phosphorylated by CDK5 at Thr1590, the unique Cdk5 phosphorylation site in the Kal-7 protein. This study was to explore the role of CDK5-mediated phosphorylation of Kal-7 in spine formation and the underlying mechanisms. Our results showed expression of Kal-7T/D (mimicked phosphorylation), Kal-7T/A mutants (blocked phosphorylation) or wild-type (Wt) Kal-7 caused in a similar increase in spine density, while spine size of Wt Kal-7-expressing cortical neurons was bigger than that in Kal-7 T\A-expressing neurons, but smaller than that in Kal-7T/D-expressing neurons. The fluorescence intensity of NMDA receptor subunit NR2B (GluN2B) staining was stronger along the MAP2 positive dendrites of Kal-7T/D-expressing neurons than that in Kal-7T/A- or Wt Kal-7-expressing neurons. The fluorescence intensity of AMPA receptor subunit GluR1 (GluA1) staining showed the same trend as GluN2B staining. These findings suggest that Cdk5 affects the function of Kal-7 on spine morphology and function via GluN2B and GluA1 receptors during dendritic spine formation.

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Acknowledgements

This work was supported by National Natural Science Foundation of China [81671338 and 81371552], Connecticut Innovation [14SCBUCHC11], and Innovation Project of Guangxi Graduate Education [T32524]. Thanks to Drs. Dick Mains and Betty Eipper for providing pEAK-myc-Kal-7, Kal-7 mutant vectors and Kal-7 antibody.

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  1. State Key Laboratory of Subtropical Agro-Bioresource Conservation and Utilization, Guangxi University, Nanning, 530004, Guangxi, China

    Ming-Xing Li & Ming Zhang

  2. College of Life Science, Shaanxi Normal University, Xi’an, 710062, Shaanxi, China

    Ming-Xing Li, Hui Qiao & Xin-Ming Ma

  3. Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, 06030, USA

    Ming-Xing Li & Xin-Ming Ma

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Li, MX., Qiao, H., Zhang, M. et al. Role of Cdk5 in Kalirin7-Mediated Formation of Dendritic Spines. Neurochem Res 44, 1243–1251 (2019). https://doi.org/10.1007/s11064-019-02771-y

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