Alzheimer’s disease risk gene BIN1 induces Tau-dependent network hyperexcitability — MEA Axion Biosciences Maestro Recordings, Figure 6

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.