Corticotropin Releasing Factor Mediates K_Ca3.1 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 with neurons from nonepileptic animals (non-SE neurons). This enhanced firing results from a cAMP-dependent protein kinase A-mediated inhibition of K_Ca3.1, a subclass of Ca²⁺-gated K⁺ channels generating the slow afterhyperpolarizing Ca²⁺-gated K⁺ current (I_sAHP). The inhibition of K_Ca3.1 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 Ca²⁺-dependent component of the slow afterhyperpolarization potential (K_Ca-sAHP). Here we show that K_Ca3.1 inhibition in post-SE neurons is induced by corticotropin releasing factor (CRF) through its Type 1 receptor (CRF₁R). Acute application of CRF₁R antagonists restores K_Ca3.1 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 CRF₁Rs 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_Ca3.1, a subtype of Ca²⁺-gated K⁺ ion channels. We show that K_Ca3.1 downregulation is mediated by corticotropin releasing factor (CRF) acting through its Type 1 receptor (CRF₁R). Congruently, acute application of selective CRF₁R antagonists restores K_Ca3.1 channel activity, leading to normalization of neuronal excitability. In the same model, injection of a CRF₁R antagonist to epileptic animals markedly decreases the frequency of electrographic seizures. Therefore, targeting CRF₁Rs may provide a new strategy in the treatment of acquired epilepsy.