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A novel role for the late-onset Alzheimer’s disease (LOAD)-associated protein Bin1 in regulating postsynaptic trafficking and glutamatergic signaling

Abstract

Postsynaptic trafficking plays a key role in regulating synapse structure and function. While spiny excitatory synapses can be stable throughout adult life, their morphology and function is impaired in Alzheimer’s disease (AD). However, little is known about how AD risk genes impact synaptic function. Here we used structured superresolution illumination microscopy (SIM) to study the late-onset Alzheimer’s disease (LOAD) risk factor BIN1, and show that this protein is abundant in postsynaptic compartments, including spines. While postsynaptic Bin1 shows colocalization with clathrin, a major endocytic protein, it also colocalizes with the small GTPases Rab11 and Arf6, components of the exocytic pathway. Bin1 participates in protein complexes with Arf6 and GluA1, and manipulations of Bin1 lead to changes in spine morphology, AMPA receptor surface expression and trafficking, and AMPA receptor-mediated synaptic transmission. Our data provide new insights into the mesoscale architecture of postsynaptic trafficking compartments and their regulation by a major LOAD risk factor.

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Acknowledgements

This work was supported by: R01s MH097216, MH107182, and MH097216 and R56 AG063433 to PP, German Research Foundation (DFG) Postdoctoral Research Fellowship SCHU2710/1-1 to BS, NS064091 MM, and NS039444 to RJW. Imaging work was partly performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Structured illumination microscopy was performed on a Nikon N-SIM system, purchased through the support of NIH 1S10OD016342-01. We thank Joshua Rappoport, Constadina Arvanitis, and Teng Leong Chew for assistance with imaging and analysis. All experiments involving animals were performed according to the Institutional Animal Care and Use Committee of NU.

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BS performed and analyzed confocal and SIM imaging experiments, some biochemistry, led the project and wrote the paper. DPB performed FRAP experiments, Arf6 activation assays, GluA1 surface expression experiments, PLA experiments, some biochemistry, data analysis and manuscript writing. KJK performed some SIM imaging. SY performed Bin1 developmental expression experiments. KM performed GluA1 surface expression experiments and FRAP experiments. KH provided general help for all experiments. CJK performed electrophysiology experiments. MDMS, MF, KRS performed biochemistry experiments. JMFP and RG performed molecular biology. MM supervised electrophysiology and advised on the project. ACB performed electron microscopy experiments. JR assisted with SIM imaging studies and data analysis. RJW supervised the electron microscopy experiments. PP supervised the project and wrote the paper.

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Correspondence to Peter Penzes.

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Schürmann, B., Bermingham, D.P., Kopeikina, K.J. et al. A novel role for the late-onset Alzheimer’s disease (LOAD)-associated protein Bin1 in regulating postsynaptic trafficking and glutamatergic signaling. Mol Psychiatry 25, 2000–2016 (2020). https://doi.org/10.1038/s41380-019-0407-3

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