Clinical evidence suggests that cortical excitability is increased in depressives. We investigated its cellular basis in a mouse model of depression. In a modified version of forced swimming (FS), mice were initially forced to swim for 5 consecutive days and then were treated daily with repetitive transcranial magnetic stimulation (rTMS) or sham treatment for the following 4 weeks without swimming. On day 2 through day 5, the mice manifested depression-like behaviors. The next and last FS was performed 4 weeks later, which revealed a 4 week maintenance of depression-like behavior in the sham mice. In slices from the sham controls, excitability in cingulate cortex pyramidal cells was elevated in terms of membrane potential and frequencies of spikes evoked by current injection. Depolarized resting potential was shown to depend on suppression of large conductance calcium-activated potassium (BK) channels. This BK channel suppression was confirmed by measuring spike width, which depends on BK channels. Chronic rTMS treatment during the 4 week period significantly reduced the depression-like behavior. In slices obtained from the rTMS mice, normal excitability and BK channel activity were recovered. Expression of a scaffold protein Homer1a was reduced by the FS and reversed by rTMS in the cingulate cortex. Similar recovery in the same behavioral, electrophysiological, and biochemical features was observed after chronic imipramine treatment. The present study demonstrated that manifestation and disappearance of depression-like behavior are in parallel with increase and decrease in cortical neuronal excitability in mice and suggested that regulation of BK channels by Homer1a is involved in this parallelism.

It is proposed that intracellular amyloid-β (Aβ), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular Aβ affects neuronal properties. This was done by injecting Aβ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular Aβ is accumulated innately. In rats, intracellular application of a mixed Aβ_1-42preparation containing both oligomers and monomers, but not a monomeric preparation of Aβ_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 Aβ_1-42. The Aβ_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 Aβ_1-42, which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the Aβ_1-42effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular Aβ_1-42is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.