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

Abstract

It is proposed that intracellular amyloid-␤ (A␤), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular A␤ affects neuronal properties. This was done by injecting A␤ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular A␤ is accumulated innately. In rats, intracellular application of a mixed A␤ 1-42 preparation containing both oligomers and monomers, but not a monomeric preparation of A␤ 1-40 , broadened spike width and augmented Ca 2ϩ influx via voltage-dependent Ca 2ϩ channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca 2ϩ -activated K ϩ (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca 2ϩ influx was caused by elongated spike duration, but not attributable to direct Ca 2ϩ channel modulation by A␤ 1-42 . The A␤ 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␤ 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␤ 1-42 effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular A␤ 1-42 is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.

Intraneuronally injected amyloid beta inhibits long-term potentiation in rat hippocampal slices

“…This intracellular scaffolding of mGluRs by the long variant Homer1 is blocked by Homer1a. Overall, the finding that one of intracellular A␤ 1-42 actions, i.e., BK channel suppression, is blocked by Homer1a (Yamamoto et al 2011) appears to be consistent with the possibility that A␤ 1-42 might act as an intracellular, as well as extracellular, scaffold for mGluRs.…”

“…It was also shown that the mGluR binding of intracellular Homer1a leads to facilitation of the BK channel (Kato 2009;Sakagami et al 2005). It has recently been shown that intracellular injection of A␤ 1-42 suppresses BK channels, which can be reversed by expression of Homer1a (Yamamoto et al 2011), suggesting an intracellular interaction between Homer1a and intracellular A␤ . Although details of such interaction are not known, the possibility arises that group I mGluRs may be the site of their intracellular interaction.…”

Increase in Cortical Pyramidal Cell Excitability Accompanies Depression-Like Behavior in Mice: A Transcranial Magnetic Stimulation Study

“…We have recently found the same suppression of BK channels and cortical hyperexcitability in 3xTg Alzheimer's model mice, which are recovered by ECS in a Homer1a-dependent manner as well (Yamamoto et al, 2011). This common abnormality in model mice for Alzheimer's and depression might serve as the target for a novel therapy that is both antidepressant and antiAlzheimer's at the same time.…”

Improvement of spatial learning by facilitating large-conductance calcium-activated potassium channel with transcranial magnetic stimulation in Alzheimer's disease model mice

“…BK channel activity was estimated by measuring the width of action potentials that are evoked in cingulate cortex pyramidal cells by 5 consecutive injections of depolarizing current at 100 Hz (Fig. 4A), since BK channel activity has a strong influence on the descending phase of spikes (Sun et al, 2011;Yamamoto et al, 2011). The width at the 5th action potential was significantly different among the 4 groups consisting of the sham and 15-Hz TMS groups of both genotypes (one-way ANOVA, F(3,71) ¼ 22.683, P ¼ 0.001).…”