Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel.
Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah School of Medicine, Jerusalem 91120, Israel
J Neurosci. 2019 Dec 11;39(50):9914-9926. doi: 10.1523/JNEUROSCI.1603-19.2019. Epub 2019 Oct 31.
Brain insults, such as trauma, stroke, anoxia, and status epilepticus (SE), cause multiple changes in synaptic function and intrinsic properties of surviving neurons that may lead to the development of epilepsy. Experimentally, a single SE episode, induced by the convulsant pilocarpine, initiates the development of an epileptic condition resembling human temporal lobe epilepsy (TLE). Principal hippocampal neurons from such epileptic animals display enhanced spike output in response to excitatory stimuli compared with neurons from nonepileptic animals. This enhanced firing is negatively related to the size of the slow afterhyperpolarization (sAHP), which is reduced in the epileptic neurons. The sAHP is an intrinsic neuronal negative feedback mechanism consisting normally of two partially overlapping components produced by disparate mechanisms. One component is generated by activation of Ca-gated K (K) channels, likely KCa3.1, consequent to spike Ca influx (the K-sAHP component). The second component is generated by enhancement of the electrogenic Na/K ATPase (NKA) by spike Na influx (NKA-sAHP component). Here we show that the K-sAHP component is markedly reduced in male rat epileptic neurons, whereas the NKA-sAHP component is not altered. The K-sAHP reduction is due to the downregulation of KCa3.1 channels, mediated by cAMP-dependent protein kinase A (PKA). This sustained effect can be acutely reversed by applying PKA inhibitors, leading also to normalization of the spike output of epileptic neurons. We propose that the novel "acquired channelopathy" described here, namely, PKA-mediated downregulation of KCa3.1 activity, provides an innovative target for developing new treatments for TLE, hopefully overcoming the pharmacoresistance to traditional drugs. Epilepsy, a common neurological disorder, often develops following a brain insult. Identifying key molecular and cellular mechanisms underlying acquired epilepsy is critical for developing effective antiepileptic therapies. In an experimental model of acquired epilepsy, we show that principal hippocampal neurons become intrinsically hyperexcitable. This alteration is due predominantly to the downregulation of a ubiquitous class of potassium ion channels, KCa3.1, whose main function is to dampen neuronal excitability. KCa3.1 downregulation is mediated by the cAMP-dependent protein kinase A (PKA) signaling pathway. Most importantly, it can be acutely reversed by PKA inhibitors, leading to recovery of KCa3.1 function and normalization of neuronal excitability. The discovery of this novel epileptogenic mechanism hopefully will facilitate the development of more efficient pharmacotherapy for acquired epilepsy.
脑损伤，如创伤、中风、缺氧和癫痫持续状态（SE），会导致存活神经元的突触功能和固有特性发生多种变化，从而导致癫痫的发生。在实验中，单次 SE 发作，由致痫剂匹罗卡品诱导，启动类似于人类颞叶癫痫（TLE）的癫痫状态的发展。来自这种癫痫动物的主要海马神经元对兴奋性刺激的尖峰输出增强，而来自非癫痫动物的神经元则增强。这种增强的放电与慢后超极化（sAHP）的大小呈负相关，而 sAHP 在癫痫神经元中减少。sAHP 是一种内在的神经元负反馈机制，通常由两种部分重叠的成分组成，这些成分是由不同的机制产生的。一个成分是由 Spike Ca 流入激活的 Ca 门控 K（K）通道（可能是 KCa3.1）产生的，这是 Spike Ca 流入的结果（K-sAHP 成分）。第二个成分是由 Spike Na 流入增强电致 Na/K ATP 酶（NKA）产生的（NKA-sAHP 成分）。在这里，我们表明，雄性大鼠癫痫神经元中的 K-sAHP 成分明显减少，而 NKA-sAHP 成分没有改变。K-sAHP 的减少是由于 cAMP 依赖性蛋白激酶 A（PKA）介导的 KCa3.1 通道下调。这种持续的效应可以通过应用 PKA 抑制剂急性逆转，也导致癫痫神经元的尖峰输出正常化。我们提出，这里描述的新型“获得性通道病”，即 PKA 介导的 KCa3.1 活性下调，为开发新的 TLE 治疗方法提供了一个创新的靶点，有望克服传统药物的耐药性。癫痫是一种常见的神经障碍，通常在脑损伤后发展。确定获得性癫痫背后的关键分子和细胞机制对于开发有效的抗癫痫治疗方法至关重要。在获得性癫痫的实验模型中，我们表明主要海马神经元内在地过度兴奋。这种改变主要是由于一类普遍存在的钾离子通道 KCa3.1 的下调所致，其主要功能是抑制神经元兴奋性。KCa3.1 的下调是由 cAMP 依赖性蛋白激酶 A（PKA）信号通路介导的。最重要的是，它可以通过 PKA 抑制剂急性逆转，导致 KCa3.1 功能的恢复和神经元兴奋性的正常化。这种新型致痫机制的发现有望促进获得性癫痫更有效的药物治疗的发展。
