Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation
| Autor: | Narayanan Kasthuri, Robert J. Andrew, Thomas Le Metayer, Vytas P. Bindokas, Ha Na Shim, Gopal Thinakaran, Sofia V. Krause, David J. Freedman, Mitchell T. Hansen, Vandana Sampathkumar, Daniel A. Nicholson, Ari Sudwarts, Anis Contractor, Nicolas Y. Masse, Timothy F. Musial, Toshihiro Nomura, Pierre De Rossi, Aleksandra J. Recupero |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Immunoelectron microscopy Presynaptic Terminals Spatial Learning Nerve Tissue Proteins Hippocampal formation Synaptic vesicle General Biochemistry Genetics and Molecular Biology Article Synapse 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Animals Neurotransmitter lcsh:QH301-705.5 Adaptor Proteins Signal Transducing Memory Consolidation Mice Knockout Neurons Neurotransmitter Agents Tumor Suppressor Proteins Brain Excitatory Postsynaptic Potentials Recognition Psychology Mice Inbred C57BL 030104 developmental biology lcsh:Biology (General) chemistry Excitatory postsynaptic potential Memory consolidation SNARE Proteins Neuroscience 030217 neurology & neurosurgery Presynaptic active zone |
| Zdroj: | Cell reports Cell Reports, Vol 30, Iss 10, Pp 3520-3535.e7 (2020) |
| ISSN: | 2211-1247 |
| Popis: | 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. Graphical Abstract In Brief 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. |
| Databáze: | OpenAIRE |
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