Alzheimer's genetic risk factor Bin1 controls synapse vesicle exo-endocytosis in inhibitory synapses

Abstract

BIN1, a late-onset Alzheimer's disease (LOAD) risk gene, is an endocytic regulator with an unclear synaptic function. We find Bin1 more prominently in inhibitory synapses (vGAT positive) than in excitatory ones (vGLUT1 positive). Bin1 knockdown reduces inhibitory synapses independently of Aβ42 production, increasing GABA release from the remaining synapses due to accelerated vGAT exocytosis and endocytosis, which decreases the size of inhibitory synaptic endosomes. In excitatory synapses, Bin1 only reduces vGLUT1 exocytosis. LOAD Bin1 mutants cannot compensate for the loss of inhibitory synapses, suggesting that these mutations are pathogenic. A loss of Bin1 function increases neuronal calcium levels and hyperexcitability, leading to elevated glutamate release due to lack of inhibition. Levetiracetam, an antiepileptic targeting presynaptic mechanisms, mitigates inhibitory synapse loss and hyperexcitability. Our findings show that Bin1 is an endocytic regulator of inhibitory synapses, link Bin1 dysfunction to neuronal hyperexcitability that contributes to Alzheimer's disease-related seizures, and emphasize levetiracetam's therapeutic potential.