Temperature elevation increases GABAA-mediated cortical inhibition in a mouse model of genetic epilepsy
Temperature elevation increases GABAA-mediated cortical inhibition in a mouse model of genetic epilepsy
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DOI：
10.1111/j.1528-1167.2010.02914.x
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发表时间：
2011-01-01
期刊：
影响因子：
5.6
通讯作者：
Petrou, Steven
中科院分区：
文献类型：
--
作者：
Hill, Elisa L.;Hosie, Suzanne;Petrou, Steven
γ-氨基丁酸（GABA）（A）受体γ 2亚单位的错义突变（R43 Q）与全身性（遗传性）癫痫伴热性惊厥加重（GEFS+）相关。与野生型同窝小鼠相比，杂合GABA（A）γ 2（R43 Q）小鼠显示出较低的热惊厥温度阈值。GABA（A）γ 2（R43 Q）受体的温度依赖性内化已被认为是该突变患者热性惊厥发生的潜在机制。我们使用GABA（A）γ 2（R43 Q）敲入小鼠模型测试了这一想法，并分析了暴露于不同温度后急性脑切片中的GABA能微型突触后抑制电流（mIPSC）。在升高的温度下孵育切片增加了杂合小鼠神经元中的mIPSC振幅，而在野生型对照中没有观察到变化。[3 H]氟马西尼结合测量全脑匀浆从突变和对照小鼠体温升高后显示没有温度依赖性差异γ 2受体密度。因此，体内小鼠数据不支持早期体外观察结果，即含有GABA（A）受体的γ 2 R43 Q的温度依赖性内化是GABA（A）γ 2（R43 Q）突变患者中热性癫痫发生的细胞机制。
P>A missense mutation (R43Q) in the gamma 2 subunit of the gamma-aminobutyric acid (GABA)(A) receptor is associated with generalized (genetic) epilepsy with febrile seizures plus (GEFS+). Heterozygous GABA(A)gamma 2(R43Q) mice displayed a lower temperature threshold for thermal seizures as compared to wild-type littermates. Temperature-dependent internalization of GABA(A)gamma 2(R43Q)-containing receptors has been proposed as a mechanism underlying febrile seizure genesis in patients with this mutation. We tested this idea using the GABA(A)gamma 2(R43Q) knockin mouse model and analyzed GABAergic miniature postsynaptic inhibitory currents (mIPSCs) in acute brain slices after exposure to varying temperatures. Incubation of slices at an elevated temperature increased mIPSC amplitude in neurons from heterozygous mice, with no change seen in wild-type controls. [3H]Flumazenil binding measured in whole-brain homogenates from mutant and control mice following elevation of body temperature showed no temperature-dependent differences in gamma 2-containing receptor density. Therefore, in vivo mouse data do not support earlier in vitro observations that proposed temperature-dependent internalization of gamma 2 R43Q containing GABA(A) receptors as the cellular mechanism underlying febrile seizure genesis in patients with the GABA(A)gamma 2(R43Q) mutation.