Alzheimer's Disease GWAS Risk Factor BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation

BIN1, a member of the BAR adaptor protein family, is a significant late-onset Alzheimer’s disease risk factor. Here, we investigated BIN1 function in the brain using conditional knockout (cKO) models. The loss of neuronal Bin1 expression resulted in select impairment of spatial learning and memory. Examination of hippocampal CA1 excitatory synapses revealed a deficit in presynaptic release probability and slower depletion of neurotransmitter during repetitive stimulation, suggesting altered vesicle dynamics in Bin1 cKO mice. Super-resolution and immunoelectron microscopy localized BIN1 to presynaptic sites in excitatory synapses. Bin1 cKO significantly reduced synapse density and altered presynaptic active zone protein cluster formation. Finally, 3D-electron microscopy reconstruction analysis uncovered a significant increase of docked and reserve pool of synaptic vesicles at hippocampal synapses in Bin1 cKO mice. Our results demonstrate a non-redundant role for BIN1 in presynaptic regulation, thus providing novel insights into BIN1's fundamental function in synaptic physiology relevant to Alzheimer’s disease.