The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome.
The serine hydrolase ABHD6 controls survival and thermally induced seizures in a mouse model of Dravet syndrome.
复制标题
DOI：
10.1016/j.nbd.2023.106099
复制
发表时间：
2023-05
影响因子：
6.1
通讯作者：
Stella, Nephi
中科院分区：
文献类型：
--
作者：
Westenbroek, Ruth;Kaplan, Joshua;Viray, Katie;Stella, Nephi
有证据表明，抑制含α/β水解酶结构域6 （ABHD6）可减少癫痫发作；然而，这种治疗反应的分子机制尚不清楚。我们发现，Abhd6 （Abhd6+/−）的杂合表达显著降低了Scn1a+/−小鼠幼崽的过早死亡率，Scn1a+/−是一种Dravet综合征（DS）的遗传小鼠模型。Abhd6+/ -突变和Abhd6的药物抑制都减少了Scn1a+/ -幼鼠热致癫痫发作的持续时间和发生率。从机制上讲，由ABHD6抑制引起的体内抗癫痫反应是由γ -氨基丁酸受体a型（GABAAR）的增强介导的。脑片电生理显示，阻断ABHD6可增强突触外（强直性）GABAAR电流，减少齿状颗粒细胞的兴奋输出，但不影响突触（相）GABAAR电流。我们的研究结果揭示了ABHD6活性和突触外GABAAR电流之间意想不到的机制联系，这种电流控制着遗传性退行性椎体滑移小鼠模型中的海马高兴奋性。这项研究提供了ABHD6活性和控制突触外GABAAR电流之间的机制联系的第一个证据，GABAAR电流控制Dravet综合征遗传小鼠模型中的海马高兴奋性，可以靶向抑制癫痫发作。
Evidence suggests that inhibition of α/β hydrolase-domain containing 6 (ABHD6) reduces seizures; however, the molecular mechanism of this therapeutic response remains unknown. We discovered that heterozygous expression of Abhd6 (Abhd6+/−) significantly reduced the premature lethality of Scn1a+/− mouse pups, a genetic mouse model of Dravet Syndrome (DS). Both Abhd6+/− mutation and pharmacological inhibition of ABHD6 reduced the duration and incidence of thermally induced seizures in Scn1a+/− pups. Mechanistically, the in vivo anti-seizure response resulting from ABHD6 inhibition is mediated by potentiation of gamma-aminobutyric acid receptors Type-A (GABAAR). Brain slice electrophysiology showed that blocking ABHD6 potentiates extrasynaptic (tonic) GABAAR currents that reduce dentate granule cell excitatory output without affecting synaptic (phasic) GABAAR currents. Our results unravel an unexpected mechanistic link between ABHD6 activity and extrasynaptic GABAAR currents that controls hippocampal hyperexcitability in a genetic mouse model of DS. This study provides the first evidence for a mechanistic link between ABHD6 activity and the control of extrasynaptic GABAAR currents that controls hippocampal hyperexcitability in a genetic mouse model of Dravet Syndrome and can be targeted to dampened seizures.
登录
查看更多内容
影响因子：
7.3
作者：
Hsu KL;Tsuboi K;Chang JW;Whitby LR;Speers AE;Pugh H;Cravatt BF
通讯作者：
Cravatt BF
Dravet综合征的临床前动物模型：癫痫发作表型，合并症和药物筛查。
影响因子：
5.6
作者：
Griffin A;Hamling KR;Hong S;Anvar M;Lee LP;Baraban SC
通讯作者：
Baraban SC
影响因子：
120.7
作者：
Chamberlain, James M.;Okada, Pamela;Baren, Jill
通讯作者：
Baren, Jill
影响因子：
5.6
作者：
Hill, Elisa L.;Hosie, Suzanne;Petrou, Steven
通讯作者：
Petrou, Steven
影响因子：
25
作者：
Kaplan, Joshua S.;Mohr, Claudia;Rossi, David J.
通讯作者：
Rossi, David J.