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Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development

Huang, Huiqian and Lin, Xiaochen and Liang, Zhuoyi and Zhao, Teng and Du, Shengwang and Loy, Michael M. T. and Lai, Kwok-On and Fu, Amy K. Y. and Ip, Nancy Y. (2017) Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development. Proceedings of the National Academy of Sciences of the United States of America, 114 (33). E6992-E7001. ISSN 0027-8424. PMCID PMC5565463. https://resolver.caltech.edu/CaltechAUTHORS:20170817-155858246

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Abstract

The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprinα1 is important for the postsynaptic organization during activity-dependent synapse development.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1708240114DOIArticle
http://www.pnas.org/content/114/33/E6992PublisherArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1708240114/-/DCSupplementalPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565463/PubMed CentralArticle
Additional Information:© 2017 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Nancy Y. Ip, July 5, 2017 (sent for review May 18, 2017; reviewed by James Bibb and Lin Mei). Published online before print July 31, 2017. We thank Dr. Jun Xia (The Hong Kong University of Science and Technology) for the HA-tagged GluA2 plasmid; Dr. Paul Greengard (Rockefeller University) for the phospho-WAVE1 antibody; Cara Kwong, Busma Butt, Nelson Hung, and Dr. Edward Tam for their excellent technical assistance; Dr. Yang Shen for professional suggestions about electrophysiology experiments; and other members of the N.Y.I. laboratory for their helpful discussions. This study was supported in part by the Research Grants Council of Hong Kong Special Administrative Region (Grants HKUST 660213, HKUST 661013, HKUST 16124616, and HKUST12/CRF/13G), the National Key Basic Research Program of China (Grant 2013CB530900), the Hong Kong Research Grants Council Theme-Based Research Scheme (Grant T13-607/12R), the Area of Excellence Scheme of the University Grants Committee (Grant AoE/M-604/16), and the Shenzhen Peacock Plan. Author contributions: H.H., K.-O.L., A.K.Y.F., and N.Y.I. designed research; H.H., X.L., Z.L., and T.Z. performed research; T.Z., S.D., and M.M.T.L. contributed new reagents/analytic tools; H.H., Z.L., K.-O.L., A.K.Y.F., and N.Y.I. analyzed data; and H.H., A.K.Y.F., and N.Y.I. wrote the paper. Reviewers: J.B., University of Alabama at Birmingham; and L.M., Medical College of Georgia. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1708240114/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
Research Grants Council of Hong Kong Special Administrative RegionHKUST 660213
Research Grants Council of Hong Kong Special Administrative RegionHKUST 661013
Research Grants Council of Hong Kong Special Administrative RegionHKUST 16124616
Research Grants Council of Hong Kong Special Administrative RegionHKUST12/CRF/13G
National Key Basic Research Program of China2013CB530900
Hong Kong Research Grants CouncilT13-607/12R
University Grants Committee (Hong Kong)AoE/M-604/16
Shenzhen Peacock PlanUNSPECIFIED
Subject Keywords:cyclin-dependent kinase 5; neurodevelopmental disorders; PSD-95; synaptic plasticity; neuronal activity
Issue or Number:33
PubMed Central ID:PMC5565463
Record Number:CaltechAUTHORS:20170817-155858246
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170817-155858246
Official Citation:Huiqian Huang, Xiaochen Lin, Zhuoyi Liang, Teng Zhao, Shengwang Du, Michael M. T. Loy, Kwok-On Lai, Amy K. Y. Fu, and Nancy Y. Ip Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development PNAS 2017 114 (33) E6992-E7001; published ahead of print July 31, 2017, doi:10.1073/pnas.1708240114
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:80584
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:17 Aug 2017 23:10
Last Modified:03 Oct 2019 18:32

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