Protein Phosphatase 2B Dual Function Facilitates Synaptic Integrity and Motor Learning
- Zhanmin Lin1,
- Bin Wu1,2,
- Maarten W. Paul3,
- Ka Wan Li4,
- Yao Yao5,
- Ihor Smal5,
- Martina Proietti Onori1,
- Hana Hasanbegovic1,
- Karel Bezstarosti6,
- Jeroen Demmers6,
- Adriaan B. Houtsmuller3,
- Erik Meijering7,
- Freek E. Hoebeek1,8,
- Martijn Schonewille1,
- August B. Smit4,
- Zhenyu Gao1, and
- Chris I. De Zeeuw1,9
- 1Department of Neuroscience, Erasmus MC, 3015 GE, Rotterdam, The Netherlands
- 2Department of Neurology and Institute of Neurology, Huashan Hospital, Fudan University, 200040, Shanghai, China
- 3Optical Imaging Center, Erasmus MC, 3015 GE, Rotterdam, The Netherlands
- 4Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam Neuroscience, 1081 HV, Amsterdam, The Netherlands
- 5Department of Medical informatics, Erasmus MC, 3015 GE, Rotterdam, The Netherlands
- 6Center for Proteomics, Erasmus MC, 3015 GE, Rotterdam, The Netherlands
- 7School of Computer Science and Engineering & Graduate School of Biomedical Engineering, University of New South Wales, Sydney, 2052, New South Wales, Australia
- 8Department for Developmental Origins of Disease, Wilhelmina Children's Hospital and Brain Center, Utrecht Medical Center, 3584 EA, Utrecht, The Netherlands
- 9Netherlands Institute for Neuroscience, KNAW, 1105 BA, Amsterdam, The Netherlands
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Author contributions: Z.L., Z.G., A.B.S., and C.I.D.Z. conceived the ideas and designed the experiments; Z.L. performed most of the experiments; M.W.P., Y.Y., M.P.O., H.H., I.S., A.B.H., and E.M. were involved in imaging experiments; B.W., F.E.H., and M.S. were involved in behavioral experiments; K.W.L., K.B., and J.D. were involved in proteomics experiments; Z.L., C.I.D.Z., A.B.S., and Z.G. wrote the manuscript with input from all authors; Z.G., A.B.S., and C.I.D.Z supervised the project.
Abstract
Protein phosphatase 2B (PP2B) is critical for synaptic plasticity and learning, but the molecular mechanisms involved remain unclear. Here we identified different types of proteins that interact with PP2B, including various structural proteins of the postsynaptic densities (PSDs) of Purkinje cells (PCs) in mice. Deleting PP2B reduced expression of PSD proteins and the relative thickness of PSD at the parallel fiber to PC synapses, whereas reexpression of inactive PP2B partly restored the impaired distribution of nanoclusters of PSD proteins, together indicating a structural role of PP2B. In contrast, lateral mobility of surface glutamate receptors solely depended on PP2B phosphatase activity. Finally, the level of motor learning covaried with both the enzymatic and nonenzymatic functions of PP2B. Thus, PP2B controls synaptic function and learning both through its action as a phosphatase and as a structural protein that facilitates synapse integrity.
SIGNIFICANCE STATEMENT Phosphatases are generally considered to serve their critical role in learning and memory through their enzymatic operations. Here, we show that protein phosphatase 2B (PP2B) interacts with structural proteins at the synapses of cerebellar Purkinje cells. Differentially manipulating the enzymatic and structural domains of PP2B leads to different phenotypes in cerebellar learning. We propose that PP2B is crucial for cerebellar learning via two complementary actions, an enzymatic and a structural operation.
- Received July 6, 2020.
- Revision received April 1, 2021.
- Accepted April 23, 2021.
- Copyright © 2021 Lin et al.
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