Abstract
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.
Highlights
Genome-wide association studies identified the BIN1 locus as a leading modulator of genetic risk in Alzheimer’s disease (AD)
BIN1 was first linked to AD in early genome-wide associated studies (GWAS) (Harold et al, 2009; Seshadri et al, 2010) and remains second only to APOE in genomewide significance in the recent meta-analysis of 94,437 individuals by the International Genomics of Alzheimer’s Disease Project (Kunkle et al, 2019)
Consistent with the increased action potential frequency observed in multielectrode arrays (MEAs) recordings (Figure 1E), higher BIN1 levels were associated with dramatically increased spontaneous excitatory postsynaptic currents (sEPSCs) frequency (Figure 2С). sEPSC amplitudes differed by
Summary
Genome-wide association studies identified the BIN1 locus as a leading modulator of genetic risk in Alzheimer’s disease (AD). Our studies revealed a role for BIN1 in regulating neuronal activity and a potential molecular mechanism involving its interactions with calcium channel subunits. We recorded action potentials and burst firing in these neurons on multielectrode arrays (MEAs) after 10 days (Figure 1AB).
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