Activation of large-conductance Ca(2+)-activated K(+) channels depresses basal synaptic transmission in the hippocampal CA1 area in APP (swe/ind) TgCRND8 mice.

Large-conductance Ca(2+)-activated K(+) (BK) channels regulate synaptic transmission by contributing to the repolarization phase of the action potential that invades the presynaptic terminal. BK channels are prone to activation under pathological conditions, such as brain ischemia and epilepsy. It is unclear if activation of these channels contributes to the depression of synaptic transmission observed in the early stage of Alzheimer's disease (AD). In this study, we recorded the field excitatory postsynaptic potentials (fEPSPs) in the hippocampus CA1 region of brain slices from 6 to 9 weeks (pre-plaque) TgCRND8 mice, a mouse model of Alzheimer's disease that harbors a double amyloid precursor mutation (KM670N/671L "Swedish" and V717F "Indiana"). Compared to age-matched controls, the fEPSPs in these animals are significantly depressed. This depression is largely mediated by the activation of presynaptic BK channels in the CA1 area. Both BK channel blockers (charybdotoxin and paxilline), and the fast binding calcium chelator, BAPTA-AM, enhance the fEPSP by deactivating the BK channels. Repetitive stimulation to the afferent pathway enhances fEPSP. This enhancement is more prominent when BK channel blockers are added in Tg slices, suggesting that repetitive stimulation further promotes BK channel activation in Tg slices. The potential candidates that mediate the activation of BK channels in these pre-plaque Alzheimer's disease model mice might involve impaired calcium homeostasis and AD related over-generation of reactive oxygen species.