Corticotropin releasing factor mediates K_Ca3.1 inhibition, hyperexcitability and seizures in acquired epilepsy

Temporal lobe epilepsy TLE, the most common focal seizure disorder in adults, can be instigated in experimental animals by convulsant-induced status epilepticus SE . Principal hippocampal neurons from SE-experienced epileptic male rats post-SE neurons display markedly augmented spike output compared to neurons from nonepileptic animals non-SE neurons . This enhanced firing results from a c-AMP-dependent protein kinase A PKA - mediated inhibition of KCa3.1, a subclass of Ca²⁺-gated K⁺ channels generating the slow afterhyperpolarizing Ca²⁺-gated K⁺ current IsAHP . The inhibition of KCa3.1 in post-SE neurons leads to a marked reduction in amplitude of the IsAHP that evolves during repetitive firing, as well as in amplitude of the associated Ca²⁺-dependent component of the slow afterhyperpolarization potential KCa-sAHP . Here we show that KCa3.1 inhibition in post-SE neurons, is induced by corticotropin releasing factor CRF through its type 1 receptor CRF1R . Acute application of CRF1R antagonists restores KCa3.1 activity in post-SE neurons, normalizing KCa-sAHP/IsAHP amplitudes and neuronal spike output, without affecting these variables in non-SE neurons. Moreover, pharmacological antagonism of CRF1Rs in vivo reduces the frequency of spontaneous recurrent seizures in post-SE chronically epileptic rats͘ These findings may provide a new vista for treating TLE.