Protein phosphatase 2b dual function facilitates synaptic integrity and motor learning

Zhanmin Lin; Bin Wu; Maarten W. Paul; Ka Wan Li; Yao Yao; Ihor Smal; Martina Proietti Onori; Hana Hasanbegovic; Karel Bezstarosti; Jeroen Demmers; Adriaan B. Houtsmuller; Erik Meijering; Freek E. Hoebeek; Martijn Schonewille; August B. Smit; Zhenyu Gao; Chris I. de Zeeuw

doi:10.1523/JNEUROSCI.1741-20.2021

Protein phosphatase 2b dual function facilitates synaptic integrity and motor learning

Zhanmin Lin, Bin Wu, Maarten W. Paul, Ka Wan Li, Yao Yao, Ihor Smal, Martina Proietti Onori, Hana Hasanbegovic, Karel Bezstarosti, Jeroen Demmers, Adriaan B. Houtsmuller, Erik Meijering, Freek E. Hoebeek, Martijn Schonewille, August B. Smit^*, Zhenyu Gao, Chris I. de Zeeuw

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	5579-5594
Number of pages	16
Journal	Journal of Neuroscience
Volume	41
Issue number	26
DOIs	https://doi.org/10.1523/JNEUROSCI.1741-20.2021
Publication status	Published - 30 Jun 2021

Bibliographical note

Funding Information:
This work was supported by EUR fellowship, Erasmus MC fellowship, NWO VENI, VIDI, and NWO-Klein grants to Z.G.; and ERC, ZonMw, NWO-ALW, ENW-Klein, Medical NeuroDelta, NIN VriendenFonds Albinisme grant, and LSH-NWO INTENSE to C.I.D.Z. We thank Mandy Rutteman and Laura Post for maintaining mouse breeding; and Elize Haasdijk and Erika Goedknegt for assistance in histology and EM. The authors declare no competing financial interests.

Publisher Copyright:
© 2021 Lin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Protein Phosphatase 2B Dual Function Facilitates SynapticFinal published version, 3.33 MBLicence: CC BY

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Lin, Z., Wu, B., Paul, M. W., Li, K. W., Yao, Y., Smal, I., Onori, M. P., Hasanbegovic, H., Bezstarosti, K., Demmers, J., Houtsmuller, A. B., Meijering, E., Hoebeek, F. E., Schonewille, M., Smit, A. B., Gao, Z., & de Zeeuw, C. I. (2021). Protein phosphatase 2b dual function facilitates synaptic integrity and motor learning. Journal of Neuroscience, 41(26), 5579-5594. https://doi.org/10.1523/JNEUROSCI.1741-20.2021

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title = "Protein phosphatase 2b dual function facilitates synaptic integrity and motor learning",

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.",

author = "Zhanmin Lin and Bin Wu and Paul, {Maarten W.} and Li, {Ka Wan} and Yao Yao and Ihor Smal and Onori, {Martina Proietti} and Hana Hasanbegovic and Karel Bezstarosti and Jeroen Demmers and Houtsmuller, {Adriaan B.} and Erik Meijering and Hoebeek, {Freek E.} and Martijn Schonewille and Smit, {August B.} and Zhenyu Gao and {de Zeeuw}, {Chris I.}",

note = "Funding Information: This work was supported by EUR fellowship, Erasmus MC fellowship, NWO VENI, VIDI, and NWO-Klein grants to Z.G.; and ERC, ZonMw, NWO-ALW, ENW-Klein, Medical NeuroDelta, NIN VriendenFonds Albinisme grant, and LSH-NWO INTENSE to C.I.D.Z. We thank Mandy Rutteman and Laura Post for maintaining mouse breeding; and Elize Haasdijk and Erika Goedknegt for assistance in histology and EM. The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2021 Lin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.",

year = "2021",

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Lin, Z, Wu, B, Paul, MW, Li, KW, Yao, Y, Smal, I, Onori, MP, Hasanbegovic, H , Bezstarosti, K , Demmers, J , Houtsmuller, AB, Meijering, E, Hoebeek, FE, Schonewille, M, Smit, AB, Gao, Z & de Zeeuw, CI 2021, 'Protein phosphatase 2b dual function facilitates synaptic integrity and motor learning', Journal of Neuroscience, vol. 41, no. 26, pp. 5579-5594. https://doi.org/10.1523/JNEUROSCI.1741-20.2021

TY - JOUR

T1 - Protein phosphatase 2b dual function facilitates synaptic integrity and motor learning

AU - Lin, Zhanmin

AU - Wu, Bin

AU - Paul, Maarten W.

AU - Li, Ka Wan

AU - Yao, Yao

AU - Smal, Ihor

AU - Onori, Martina Proietti

AU - Hasanbegovic, Hana

AU - Bezstarosti, Karel

AU - Demmers, Jeroen

AU - Houtsmuller, Adriaan B.

AU - Meijering, Erik

AU - Hoebeek, Freek E.

AU - Schonewille, Martijn

AU - Smit, August B.

AU - Gao, Zhenyu

AU - de Zeeuw, Chris I.

N1 - Funding Information: This work was supported by EUR fellowship, Erasmus MC fellowship, NWO VENI, VIDI, and NWO-Klein grants to Z.G.; and ERC, ZonMw, NWO-ALW, ENW-Klein, Medical NeuroDelta, NIN VriendenFonds Albinisme grant, and LSH-NWO INTENSE to C.I.D.Z. We thank Mandy Rutteman and Laura Post for maintaining mouse breeding; and Elize Haasdijk and Erika Goedknegt for assistance in histology and EM. The authors declare no competing financial interests. Publisher Copyright: © 2021 Lin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

PY - 2021/6/30

Y1 - 2021/6/30

N2 - 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.

AB - 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.

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JO - Journal of Neuroscience

JF - Journal of Neuroscience

IS - 26

ER -

Protein phosphatase 2b dual function facilitates synaptic integrity and motor learning

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