Perlin J B, Churn S B, Lothman E W, DeLorenzo R J
Department of Neurology, Medical College of Virginia, Richmond 23298.
Epilepsy Res. 1992 Apr;11(2):111-8. doi: 10.1016/0920-1211(92)90045-u.
Understanding the molecular basis of altered neuronal excitability in epilepsy is a major challenge in neuroscience research. The present study suggests an inverse correlation between changes in neuronal excitability in status epilepticus and the activity of type II multifunctional calcium/calmodulin-dependent kinase II (CaM kinase II), a major Ca(2+)-signal transducing system in brain. 'Continuous' hippocampal stimulation (CHS), a new model of non-convulsive limbic status epilepticus (SE), mimics the progression of electrographic changes characteristic in human SE and allows for quantitation of post-stimulus seizure severity. In the present study, hippocampus and anterior neocortex from CHS-stimulated rats and paired surgical controls were assayed for CaM kinase II activity by incorporation of radiolabeled phosphate from [gamma-32P]ATP into the 50-kDa subunit of the kinase itself (autophosphorylation). In all instances, CHS induced sustained interictal bursting and/or electrographic seizures. Decreased CaM kinase II activity was seen in all preparations from electrically stimulated hippocampus. CaM kinase II activity in CHS animals was diminished by 37% relative to controls (P less than 0.01; Student's paired t-test). The progressive intensity of the EEG discharges correlated directly with the decrement of CaM kinase II activity (P less than 0.05; Spearman's rank correlation test, n = 5). This is the first report of a dynamic modulation of a biochemical system that has been implicated in neuronal excitability in coordination with the characterized developmental stages of SE.
了解癫痫中神经元兴奋性改变的分子基础是神经科学研究中的一项重大挑战。本研究表明，癫痫持续状态下神经元兴奋性的变化与II型多功能钙/钙调蛋白依赖性激酶II（CaM激酶II）的活性呈负相关，CaM激酶II是大脑中主要的Ca(2+)信号转导系统。“连续”海马刺激（CHS）是一种非惊厥性边缘性癫痫持续状态（SE）的新模型，它模拟了人类SE中特征性的脑电图变化进程，并允许对刺激后癫痫发作严重程度进行定量分析。在本研究中，通过将[γ-32P]ATP中的放射性标记磷酸盐掺入激酶自身的50 kDa亚基（自磷酸化），对CHS刺激大鼠和配对手术对照的海马及前新皮质进行了CaM激酶II活性检测。在所有情况下，CHS均诱发了持续性发作间期爆发和/或脑电图癫痫发作。在电刺激海马的所有标本中均观察到CaM激酶II活性降低。CHS动物的CaM激酶II活性相对于对照组降低了37%（P<0.01；学生配对t检验）。脑电图放电的渐进强度与CaM激酶II活性的降低直接相关（P<0.05；Spearman等级相关检验，n = 5）。这是关于一个生化系统动态调节的首次报道，该生化系统与SE的特征性发育阶段协同作用，参与了神经元兴奋性的调节。
