Corticotropin releasing factor mediates KCa3.1 inhibition, hyperexcitability and seizures in acquired epilepsy

Abstract

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.