Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation
Pierre De Rossi,
Toshihiro Nomura,
Robert J. Andrew,
Nicolas Y. Masse,
Vandana Sampathkumar,
Timothy F. Musial,
Ari Sudwarts,
Aleksandra J. Recupero,
Thomas Le Metayer,
Mitchell T. Hansen,
Ha-Na Shim,
Sofia V. Krause,
David J. Freedman,
Vytas P. Bindokas,
Narayanan Kasthuri,
Daniel A. Nicholson,
Anis Contractor,
Gopal Thinakaran
Affiliations
Pierre De Rossi
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Toshihiro Nomura
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Robert J. Andrew
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Nicolas Y. Masse
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Vandana Sampathkumar
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Timothy F. Musial
Department of Neurological sciences, Rush University, Chicago, IL 60612, USA
Ari Sudwarts
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA; Department of Molecular Medicine and Byrd Alzheimer’s Institute, University of South Florida, Tampa, FL 33613, USA
Aleksandra J. Recupero
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Thomas Le Metayer
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Mitchell T. Hansen
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA; Department of Molecular Medicine and Byrd Alzheimer’s Institute, University of South Florida, Tampa, FL 33613, USA
Ha-Na Shim
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Sofia V. Krause
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA
David J. Freedman
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Vytas P. Bindokas
Integrated Light Microscopy Facility, The University of Chicago, Chicago, IL 60637, USA
Narayanan Kasthuri
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Daniel A. Nicholson
Department of Neurological sciences, Rush University, Chicago, IL 60612, USA
Anis Contractor
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Neurobiology, Weinberg College of Arts and Sciences, Northwestern University, Chicago, IL, USA
Gopal Thinakaran
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA; Department of Neurology, The University of Chicago, Chicago, IL 60637, USA; Department of Pathology, The University of Chicago, Chicago, IL 60637, USA; Department of Molecular Medicine and Byrd Alzheimer’s Institute, University of South Florida, Tampa, FL 33613, USA; Corresponding author
Summary: BIN1, a member of the BAR adaptor protein family, is a significant late-onset Alzheimer disease risk factor. Here, we investigate BIN1 function in the brain using conditional knockout (cKO) models. Loss of neuronal Bin1 expression results in the select impairment of spatial learning and memory. Examination of hippocampal CA1 excitatory synapses reveals a deficit in presynaptic release probability and slower depletion of neurotransmitters during repetitive stimulation, suggesting altered vesicle dynamics in Bin1 cKO mice. Super-resolution and immunoelectron microscopy localizes BIN1 to presynaptic sites in excitatory synapses. Bin1 cKO significantly reduces synapse density and alters presynaptic active zone protein cluster formation. Finally, 3D electron microscopy reconstruction analysis uncovers a significant increase in docked and reserve pools of synaptic vesicles at hippocampal synapses in Bin1 cKO mice. Our results demonstrate a non-redundant role for BIN1 in presynaptic regulation, thus providing significant insights into the fundamental function of BIN1 in synaptic physiology relevant to Alzheimer disease. : BIN1 is a significant risk factor for late-onset Alzheimer disease. BIN1 has a general role in endocytosis and membrane dynamics in non-neuronal cells. De Rossi et al. show that BIN1 localizes to presynaptic terminals and plays an indispensable role in excitatory synaptic transmission by regulating neurotransmitter vesicle dynamics. Keywords: late-onset Alzheimer disease, BIN1, Morris water maze, synaptic physiology, release probability, super-resolution, dSTORM, STED, 3D EM reconstruction, Amphiphysin 2
