Alzheimer’s disease risk gene BIN1 modulates neural network activity through the regulation of L-type calcium channel expression in human induced neurons

AbstractBridging Integrator 1 (BIN1) is the second most important Alzheimer’s disease (AD) risk gene after APOE, but its physiological roles and contribution to brain pathology are largely elusive. In this work, we tackled the short- and long-term effects of BIN1 deletion in human induced neurons (hiNs) grown in bi-dimensional cultures and in cerebral organoids. We show that BIN1 loss-of-function leads to specific transcriptional alterations in glutamatergic neurons involving mainly genes associated with calcium homeostasis, ion transport and synapse function. We also show that BIN1 regulates calcium transients and neuronal electrical activity through interaction with the L-type voltage-gated calcium channel Cav1.2 and regulation of activity-dependent internalization of this channel. Treatment with the Cav1.2 antagonist nifedipine partly rescues neuronal electrical alterations in BIN1 knockout hiNs. Together, our results indicate that BIN1 misexpression impairs calcium homeostasis in glutamatergic neurons, potentially contributing to the transcriptional changes and neural network dysfunctions observed in AD.