Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.
Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.
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DOI：
10.1126/scitranslmed.3004190
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发表时间：
2012-11-21
影响因子：
17.1
通讯作者：
Kullmann DM
中科院分区：
文献类型：
--
作者：
Wykes RC;Heeroma JH;Mantoan L;Zheng K;MacDonald DC;Deisseroth K;Hashemi KS;Walker MC;Schorge S;Kullmann DM
新皮质癫痫通常具有抗药性。手术切除致痫区仅在少数病例中可行，使许多患者无法获得有效治疗。我们报告了基因治疗在局灶性新皮层癫痫中的潜在疗效，该癫痫是通过在运动皮层注射破伤风毒素诱导的啮齿动物模型。通过应用几种互补的方法，使用连续无线脑电图监测来量化癫痫活动，我们观察到高频活动和癫痫样事件的发生率增加。癫痫灶中的锥体神经元表现出与癫痫发作一致的增强的内在兴奋性。光遗传抑制的一个子集的主要神经元转导的盐视紫红质靶向癫痫灶的慢病毒递送足以减弱脑电图癫痫发作。钾通道Kv1.1的局部慢病毒过表达降低了转导的锥体神经元的内在兴奋性。共注射该Kv1.1慢病毒与破伤风毒素完全防止了脑电图癫痫发作的发生。最后，将Kv1.1慢病毒给予已建立的癫痫病灶，在几周内逐渐抑制癫痫活动，而没有可检测到的行为副作用。因此，啮齿动物模型中的基因治疗可用于急性抑制癫痫发作，防止癫痫刺激后癫痫发作的发生，并成功治疗已建立的局灶性癫痫。
Neocortical epilepsy is frequently drug-resistant. Surgery to remove the epileptogenic zone is only feasible in a minority of cases, leaving many patients without an effective treatment. We report the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model in which epilepsy is induced by tetanus toxin injection in the motor cortex. By applying several complementary methods that use continuous wireless electroencephalographic monitoring to quantify epileptic activity, we observed increases in high frequency activity and in the occurrence of epileptiform events. Pyramidal neurons in the epileptic focus showed enhanced intrinsic excitability consistent with seizure generation. Optogenetic inhibition of a subset of principal neurons transduced with halorhodopsin targeted to the epileptic focus by lentiviral delivery was sufficient to attenuate electroencephalographic seizures. Local lentiviral overexpression of the potassium channel Kv1.1 reduced the intrinsic excitability of transduced pyramidal neurons. Coinjection of this Kv1.1 lentivirus with tetanus toxin fully prevented the occurrence of electroencephalographic seizures. Finally, administration of the Kv1.1 lentivirus to an established epileptic focus progressively suppressed epileptic activity over several weeks without detectable behavioral side effects. Thus, gene therapy in a rodent model can be used to suppress seizures acutely, prevent their occurrence after an epileptogenic stimulus, and successfully treat established focal epilepsy.
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