Figure 7.
CaN inhibition and p38 MAPK activation reverse downregulated HCN channel gating and neuronal hyperexcitability in epileptic animals. A, Application of either CaN inhibitor FK506 (epileptic+FK506) or p38 MAPK activator anisomycin (epileptic+ani) partially reversed the hyperpolarized shift in Ih voltage-dependent activation toward control levels in dendrites of CA1 hippocampal pyramidal neurons from chronically epileptic animals. Coapplication of anisomycin and FK506 (epileptic+ani+FK506) restored HCN channel gating nearly to control levels. B, Current-clamp recordings in pyramidal neuron dendrites from chronically epileptic animals showed decreased IR following coapplication of FK506 and anisomycin compared with untreated epileptic tissue. Representative dendritic current-clamp recordings in response to 100 pA hyperpolarizing current injection are shown. All recordings in B–D were performed with resting potential held at −65 mV, and dendritic recording distances in representative traces under drug-treated and untreated epileptic conditions were 180 and 170 μm, respectively. C, TS of five 20 Hz α-EPSP current injections in pyramidal neuron dendrites in epileptic tissue after treatment with anisomycin and FK506 was not significantly different from TS in pyramidal neuron dendrites under untreated epileptic conditions. D, AP firing from depolarizing dendritic current injections (500 ms) in pyramidal neurons from epileptic tissue following coapplication of FK506 and anisomycin showed significantly decreased excitability (*p < 0.05) that was similar to control levels. Representative traces show decreased dendritic backpropagating AP firing from dendritic current injection (700 pA) in drug-treated epileptic conditions compared with untreated epileptic conditions.