BIN1 regulates electrical activity and network synchronization in hiPSC-derived neurons

Alzheimer disease (AD) is a multifactorial disease with a strong genetic background. Recent genomic wide association studies have identified several loci linked to an increased risk of AD. However, genes regulated by these variants and the pathophysiological mechanisms regulated by those genes remain largely elusive. In this work, we studied the role of Bridging Integrator 1 (BIN1), the second most important AD risk gene after APOE, in neurons generated from human induced pluripotent stem cells (hiPSCs) in bi-dimensional cultures and cerebral organoids. We show that deletion of BIN1 is sufficient to cause neuronal hyperactivation and network desynchronization in a cell-autonomous fashion. These functional changes are correlated with increased Tau phosphorylation and transcriptional changes similar to those observed in the brains of AD patients, particularly in glutamatergic neurons. Together, our results reveal a role for BIN1 in the regulation of electrical activity in human neurons and suggest that its implication in AD pathogenesis could be related to the neuronal and network dysfunctions observed in the AD brain. ### Competing Interest Statement The authors have declared no competing interest.