Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a

It is proposed that intracellular amyloid-beta (A beta), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular A beta affects neuronal properties. This was done by injecting A beta protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular A beta is accumulated innately. In rats, intracellular application of a mixed A beta(1-42) preparation containing both oligomers and monomers, but not a monomeric preparation of A beta(1-40), broadened spike width and augmented Ca2+ influx via voltage-dependent Ca2+ channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca2+-activated K+ (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca2+ influx was caused by elongated spike duration, but not attributable to direct Ca2+ channel modulation by A beta(1-42). The A beta(1-42)-induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by A beta(1-42), which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the A beta(1-42) effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular A beta(1-42) is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.