Corticotropin Releasing Factor Mediates K Ca 3.1 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 with neurons from nonepileptic animals (non-SE neurons). This enhanced firing results from a cAMP-dependent protein kinase A-mediated inhibition of K Ca 3.1, a subclass of Ca 2+ -gated K + channels generating the slow afterhyperpolarizing Ca 2+ -gated K + current ( I sAHP ). The inhibition of K Ca 3.1 in post-SE neurons leads to a marked reduction in amplitude of the I sAHP that evolves during repetitive firing, as well as in amplitude of the associated Ca 2+ -dependent component of the slow afterhyperpolarization potential (K Ca -sAHP). Here we show that K Ca 3.1 inhibition in post-SE neurons is induced by corticotropin releasing factor (CRF) through its Type 1 receptor (CRF 1 R). Acute application of CRF 1 R antagonists restores K Ca 3.1 activity in post-SE neurons, normalizing K Ca -sAHP/ I sAHP amplitudes and neuronal spike output, without affecting these variables in non-SE neurons. Moreover, pharmacological antagonism of CRF 1 Rs in vivo reduces the frequency of spontaneous recurrent seizures in post-SE chronically epileptic rats. These findings may provide a new vista for treating TLE. SIGNIFICANCE STATEMENT Epilepsy, a common neurologic disorder, often develops following a brain insult. Identifying key cellular mechanisms underlying acquired epilepsy is critical for developing effective antiepileptic therapies. In an experimental model of acquired epilepsy, principal hippocampal neurons manifest hyperexcitability because of downregulation of K Ca 3.1, a subtype of Ca 2+ -gated K + ion channels. We show that K Ca 3.1 downregulation is mediated by corticotropin releasing factor (CRF) acting through its Type 1 receptor (CRF 1 R). Congruently, acute application of selective CRF 1 R antagonists restores K Ca 3.1 channel activity, leading to normalization of neuronal excitability. In the same model, injection of a CRF 1 R antagonist to epileptic animals markedly decreases the frequency of electrographic seizures. Therefore, targeting CRF 1 Rs may provide a new strategy in the treatment of acquired epilepsy.