PICK1 uncoupling from mGluR7a causes absence-like seizures.
PICK1 uncoupling from mGluR7a causes absence-like seizures.
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DOI：
10.1038/nn.2142
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发表时间：
2008-08
影响因子：
25
通讯作者：
Lerner-Natoli, Mireille
中科院分区：
文献类型：
--
作者：
Bertaso, Federica;Zhang, Chuansheng;Scheschonka, Astrid;de Bock, Frederic;Fontanaud, Pierre;Marin, Philippe;Huganir, Richard L.;Betz, Heinrich;Bockaert, Joeal;Fagni, Laurent;Lerner-Natoli, Mireille
失神性癫痫是一种神经系统疾病，会导致反复意识丧失和脑电图 (EEG) 上出现普遍的棘波放电。迄今为止，代谢型谷氨酸受体（mGluR）和相关支架蛋白在失神性癫痫中的作用尚不清楚。我们研究了这些蛋白在失神性癫痫中的可能作用，重点关注大鼠和小鼠中的 mGluR7a 受体及其 PDZ 相互作用蛋白，即与 C 激酶 1 (PICK1) 相互作用的蛋白。注射细胞渗透性显性失活肽或 mGluR7a C 末端的靶向突变，两者都会破坏受体和 PDZ 蛋白之间的相互作用，引起行为症状和脑电图放电，这是失神性癫痫的特征。 Pick1 基因的失活也促进了失神癫痫表型的药理学诱导。已知参与失神性癫痫的皮质和丘脑参与其中，但海马体则不然。我们的结果表明，mGluR7a-PICK1 复合物的破坏足以在大鼠和小鼠中诱导失神性癫痫样癫痫发作，因此据我们所知，提供了第一个在失神性癫痫中代谢型谷氨酸受体与 PDZ 蛋白相互作用的动物模型。
Absence epilepsy is a neurological disorder that causes a recurrent loss of consciousness and generalized spike-and-wave discharges on an electroencephalogram (EEG). The role of metabotropic glutamate receptors (mGluRs) and associated scaffolding proteins in absence epilepsy has been unclear to date. We investigated a possible role for these proteins in absence epilepsy, focusing on the mGluR7a receptor and its PDZ-interacting protein, protein interacting with C kinase 1 (PICK1), in rats and mice. Injection of a cell-permeant dominant-negative peptide or targeted mutation of the mGluR7a C terminus, both of which disrupt the interaction between the receptor and PDZ proteins, caused behavioral symptoms and EEG discharges that are characteristic of absence epilepsy. Inactivation of the Pick1 gene also facilitated pharmacological induction of the absence epilepsy phenotype. The cortex and thalamus, which are known to participate in absence epilepsy, were involved, but the hippocampus was not. Our results indicate that disruption of the mGluR7a-PICK1 complex is sufficient to induce absence epilepsy—like seizures in rats and mice, thus providing, to the best of our knowledge, the first animal model of metabotropic glutamate receptor—PDZ protein interaction in absence epilepsy.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
3.4
作者：
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通讯作者：
Nehlig, A