Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, United States
Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, United States
J Nicholas Cochran
Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, United States
Travis Rush
Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, United States
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, United States
Jacob S Mesina
Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, United States
Mohammad Waqas
Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, United States
Rachael M Vollmer
Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, United States
Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, United States
Genome-wide association studies identified the BIN1 locus as a leading modulator of genetic risk in Alzheimer’s disease (AD). One limitation in understanding BIN1’s contribution to AD is its unknown function in the brain. AD-associated BIN1 variants are generally noncoding and likely change expression. Here, we determined the effects of increasing expression of the major neuronal isoform of human BIN1 in cultured rat hippocampal neurons. Higher BIN1 induced network hyperexcitability on multielectrode arrays, increased frequency of synaptic transmission, and elevated calcium transients, indicating that increasing BIN1 drives greater neuronal activity. In exploring the mechanism of these effects on neuronal physiology, we found that BIN1 interacted with L-type voltage-gated calcium channels (LVGCCs) and that BIN1–LVGCC interactions were modulated by Tau in rat hippocampal neurons and mouse brain. Finally, Tau reduction prevented BIN1-induced network hyperexcitability. These data shed light on BIN1’s neuronal function and suggest that it may contribute to Tau-dependent hyperexcitability in AD.
