Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice
Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice
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DOI：
10.1523/jneurosci.3456-16.2017
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发表时间：
2017-08-23
影响因子：
5.3
通讯作者：
Sperk, Gunther
中科院分区：
文献类型：
--
作者：
Drexel, Meinrad;Romanov, Roman A.;Sperk, Gunther
颞叶癫痫（TLE）是局灶性癫痫最常见的形式，通常与海马结构的功能障碍有关。最近，在TLE患者的下托和TLE动物模型中观察到了小清蛋白（PV）神经元的优先损失。为了证明一个可能的致病作用，在产生的TLE的功能不全的PV神经元，我们永久抑制GABA的释放选择性的PV神经元腹侧下托注射表达破伤风毒素轻链的病毒载体在雄性小鼠。随后，对小鼠进行遥测EEG记录和视频监测。88%的小鼠出现簇状棘波放电（C-SWD; 40.0 +/- 9.07/月），64%的小鼠出现自发性复发性癫痫发作（SRS; 5.3 +/- 0.83/月）。用对照载体注射的小鼠既不呈现C-SWD也不呈现SRS。由于载体注射或SRS，观察到神经变性。有趣的是，仅表现出C-SWD但没有SRS的小鼠在6周后注射亚惊厥剂量的戊四唑后产生SRS。5周后，SRS的初始频率下降了约30%。与PV神经元的永久沉默相反，通过在含PV神经元中选择性表达的设计者受体hM 4Di从PV神经元释放GABA的瞬时抑制瞬时降低了小鼠的癫痫发作阈值，但既不诱导急性癫痫发作也不诱导复发性癫痫发作。我们的数据表明，一个关键的作用，由PV介导的体周抑制含中间神经元，这表明他们的持续沉默可能是因果关系参与TLE的发展。
Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 +/- 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 +/- 0.83/month). Mice injected with a control vector presented with neitherC-SWDsnor SRSs. Noneurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by similar to 30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE.