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Cell Rep. 2020 Mar 10;30(10):3520-3535.e7. doi: 10.1016/j.celrep.2020.02.026.

Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation.

Author information

1
Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA.
2
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
3
Department of Neurological sciences, Rush University, Chicago, IL 60612, USA.
4
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.
5
Integrated Light Microscopy Facility, The University of Chicago, Chicago, IL 60637, USA.
6
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.
7
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. Electronic address: thinakaran@usf.edu.

Abstract

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.

KEYWORDS:

3D EM reconstruction; Amphiphysin 2; BIN1; Morris water maze; STED; dSTORM; late-onset Alzheimer disease; release probability; super-resolution; synaptic physiology

PMID:
32160554
DOI:
10.1016/j.celrep.2020.02.026
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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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