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.

颞叶癫痫 (TLE) 是成人中最常见的局灶性癫痫发作，可通过惊厥诱发的癫痫持续状态 (SE) 在实验动物中引发。与非癫痫动物的神经元（非 SE 神经元）相比，经历过 SE​​ 的雄性癫痫大鼠的主要海马神经元（后 SE 神经元）显示出明显增强的尖峰输出。这种增强的放电是由 cAMP 依赖性蛋白激酶 A 介导的 K _{Ca 3.1 抑制作用引起的，K Ca 3.1 是 Ca} ²⁺门控 K ⁺通道的一个子类，产生缓慢的后超极化 Ca ²⁺门控 K ⁺电流 ( I _sAHP )。_{K Ca}的抑制3.1 在后 SE 神经元中导致在重复放电过程中演变的I _sAHP的振幅显着降低，以及相关的 Ca ²⁺的振幅 -慢后超极化电位 (K _Ca -sAHP) 的依赖性分量。在这里，我们表明促肾上腺皮质激素释放因子 (CRF) 通过其 1 型受体 (CRF ₁ R)诱导 SE 后神经元中的K _{Ca 3.1 抑制。}CRF ₁ R 拮抗剂的急性应用可恢复 SE 后神经元中的 K _Ca 3.1 活性，使 K _Ca -sAHP/ I _{sAHP 正常化}振幅和神经元尖峰输出，而不影响非 SE 神经元中的这些变量。此外，CRF ₁ Rs在体内的药理学拮抗作用降低了 SE 后慢性癫痫大鼠自发性复发性癫痫发作的频率。这些发现可能为治疗 TLE 提供新的前景。

意义声明癫痫是一种常见的神经系统疾病，通常在脑损伤后发展。确定获得性癫痫背后的关键细胞机制对于开发有效的抗癫痫疗法至关重要。在获得性癫痫的实验模型中，由于 K _{Ca 3.1（Ca} ²⁺门控 K ⁺离子通道的一种亚型）的下调，主要海马神经元表现出过度兴奋。我们表明，K _Ca 3.1 下调是由促肾上腺皮质激素释放因子 (CRF) 通过其 1 型受体 (CRF ₁ R) 介导的。一致地，急性应用选择性 CRF ₁ R 拮抗剂可恢复 K _Ca3.1 通道活动，导致神经元兴奋性正常化。在同一模型中，向癫痫动物注射 CRF ₁ R 拮抗剂可显着降低脑电图发作的频率。因此，靶向CRF ₁ Rs可能为获得性癫痫的治疗提供新的策略。