Targeted Interneuron Ablation in the Mouse Hippocampus Can Cause Spontaneous Recurrent Seizures.
Targeted Interneuron Ablation in the Mouse Hippocampus Can Cause Spontaneous Recurrent Seizures.
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DOI：
10.1523/eneuro.0130-17.2017
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发表时间：
2017-07
期刊：
影响因子：
3.4
通讯作者：
Dudek FE
中科院分区：
文献类型：
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作者：
Spampanato J;Dudek FE
GABA能中间神经元的死亡长期以来一直被假设为导致获得性癫痫。这些实验测试了局灶性中间神经元损伤引起急性癫痫发作的假设[即，癫痫持续状态（SE）]和/或慢性癫痫[即，持续性自发复发性癫痫发作（SRS）。为了选择性地消融中间神经元，Gad 2-ires-Cre小鼠在背侧海马的CA 1区单侧注射含有白喉毒素受体（DTR）的腺相关病毒。同时，将连接到微型遥测装置的电极定位在注射部位，用于长期记录局部场电位（LFP）。病毒转染两周后，腹腔内注射DT持续引起中间神经元的局灶性、特异性和广泛的消融。长期连续监测显示，所有DT诱导的中间神经元病变的小鼠都有SRS。癫痫发作持续数十秒，发作间期为数小时（或数天）;因此，这些中间神经元病变不会诱导SE。SRS发生在DT治疗后3-5天，这是DT诱导细胞死亡所需的估计时间;因此，SRS的诱导发生在没有获得性癫痫典型的潜伏期的情况下。在六只DT治疗的小鼠中，有五只在几天内停止了SRS，这表明DT诱导的中间神经元病变通常不会引起癫痫。然而，在一只小鼠中，在中间神经元消融后发生SRS ≥34 d，类似于实验性SE后的癫痫。假手术对照小鼠没有可检测到的癫痫发作，证实SRS是由于中间神经元的消融。这些数据表明，选择性中间神经元消融一致地引起SRS而不是SE;并且，至少在本文使用的条件下，中间神经元损伤很少导致持续性SRS（即，癫痫）。
The death of GABAergic interneurons has long been hypothesized to contribute to acquired epilepsy. These experiments tested the hypothesis that focal interneuron lesions cause acute seizures [i.e., status epilepticus (SE)] and/or chronic epilepsy [i.e., persistent spontaneous recurrent seizures (SRSs)]. To selectively ablate interneurons, Gad2-ires-Cre mice were injected unilaterally in the CA1 area of the dorsal hippocampus with an adeno-associated virus containing the diphtheria toxin receptor (DTR). Simultaneously, an electrode, connected to a miniature telemetry device, was positioned at the injection site for chronic recordings of local field potentials (LFPs). Two weeks after virus transfection, intraperitoneal injection of DT consistently caused focal, specific, and extensive ablation of interneurons. Long-term, continuous monitoring revealed that all mice with DT-induced interneuron lesions had SRSs. Seizures lasted tens of seconds and interseizure intervals were several hours (or days); therefore, these interneuron lesions did not induce SE. The SRSs occurred 3-5 d after DT treatment, which is the estimated time required for DT-induced cell death; therefore, induction of SRSs occurred without the latent period typical of acquired epilepsy. In five of six DT-treated mice, SRSs stopped within days, suggesting that the DT-induced interneuron lesions did not usually cause epilepsy. In one mouse, however, SRSs occurred for ≥34 d after interneuron ablation, similar to epilepsy after experimental SE. Sham control mice had no detectable seizures, confirming that the SRSs were due to ablation of interneurons. These data show that selective interneuron ablation consistently caused SRSs but not SE; and, at least under the conditions used here, interneuron lesions rarely led to persistent SRSs (i.e., epilepsy).