Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy
Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy
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DOI：
10.1073/pnas.0608215103
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发表时间：
2006-12-12
影响因子：
11.1
通讯作者：
Boulter, Jim
中科院分区：
文献类型：
--
作者：
Klaassen, Alwin;Glykys, Joseph;Boulter, Jim
人类α - 4或β - 2神经元烟碱乙酰胆碱受体亚基基因的选择性突变与常染色体显性夜间额叶癫痫（ADNFLE）的部分癫痫综合征共分离。为了研究这种遗传性癫痫的可能机制，我们在小鼠中设计了两个ADNFLE突变（Chrna4（S252F）和Chrna4(+L264)）。杂合子ADNFLE突变小鼠表现出持续的、异常的皮质脑电图，具有显著的δ和θ频率，表现出频繁的自发癫痫发作，并表现出对尼古丁的前惊厥作用的敏感性增加。与WT相比，ADNFLE小鼠II/III层皮质锥体细胞的电生理记录显示尼古丁诱发的抑制性突触后电流增加了约20倍，而对兴奋性突触后电流没有影响。在ADNFLE突变小鼠中，腹腔注射低于阈值剂量的微毒素（一种使用依赖性γ -氨基丁酸受体拮抗剂）可降低皮质脑电图δ功率并短暂抑制自发癫痫发作活动。我们的研究表明，ADNFLE癫痫发作的机制可能涉及皮质网络的抑制性同步，通过激活位于皮质gaba能中间神经元的突触前终末和躯体-树突状隔室的含有突变α 4的尼古丁乙酰胆碱受体。
Selected mutations in the human alpha 4 or beta 2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4(S252F) and Chrna4(+L264)) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II/III cortical pyramidal cells reveal a > 20-fold increase in nicotine-evoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of picrotoxin, a use-dependent gamma-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant alpha 4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somato-dendritic compartments of cortical GABAergic interneurons.