Cortical alterations in a model for absence epilepsy and febrile seizures: In vivo findings in mice carrying a human GABA(A)R gamma2 subunit mutation
Cortical alterations in a model for absence epilepsy and febrile seizures: In vivo findings in mice carrying a human GABA(A)R gamma2 subunit mutation
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DOI：
10.1016/j.nbd.2015.02.018
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发表时间：
2015-05
影响因子：
6.1
通讯作者：
J. Witsch;D. Golkowski;Thomas T. G. Hahn;S. Petrou;H. Spors
中科院分区：
文献类型：
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作者：
J. Witsch;D. Golkowski;Thomas T. G. Hahn;S. Petrou;H. Spors
儿童失神性癫痫（CAE）是儿童癫痫最常见的形式之一。对一个澳大利亚大家族的研究表明，编码GABA（A）受体γ 2亚单位（G2 R43 Q）的基因中的点突变导致常染色体显性遗传形式的CAE和热性惊厥（FS）。在携带γ 2（R43 Q）突变的转基因小鼠模型中，杂合动物重现了人类表型。体外实验表明，这种点突变损害皮层抑制，从而增加了癫痫发作的可能性。在这里，使用全细胞（WC）和细胞外（EC）记录以及电压敏感染料成像（VSDI），我们系统地寻找在体内相关的G2 R43 Q突变引起的皮层改变，所提出的体外结果。我们测量了自发和胡须诱发活动的初级躯体感觉皮层和腹后内侧核的丘脑（VPM）之前和之后腹腔注射致癫痫物质戊四氮（PTZ）在麻醉的G2 R43 Q小鼠和对照组在一个盲目的设置。2.增加2/3层和5/6层锥体神经元中的皮质自发活动（增加WC记录中平均膜电位的标准差），2.）VSDI实验中刺激诱发的皮质反应的变化增加。3.）第三章皮质效应不是由于丘脑输出的强度或精度增加。总之，我们的研究结果支持了人类遗传性失神癫痫小鼠模型中皮质病理学的假设。需要进一步的研究来表征潜在的分子机制。
Childhood absence epilepsy (CAE) is one of the most common forms of epilepsy among children. The study of a large Australian family demonstrated that a point mutation in the gene encoding the gamma2 subunit of the GABA(A) receptor (G2R43Q) leads to an autosomal dominantly inherited form of CAE and febrile seizures (FS). In a transgenic mouse model carrying the gamma2 (R43Q) mutation heterozygous animals recapitulate the human phenotype. In-vitro experiments indicated that this point mutation impairs cortical inhibition and thus increases the likelihood of seizures.Here, using whole-cell (WC) and extracellular (EC) recordings as well as voltage-sensitive dye imaging (VSDI), we systematically searched for an in vivo correlate of cortical alterations caused by the G2R43Q mutation, as suggested by the mentioned in vitro results. We measured spontaneous and whisker-evoked activity in the primary somatosensory cortex and ventral posteriomedial nucleus of the thalamus (VPM) before and after intraperitoneal injection of the ictogenic substance pentylenetetrazol (PTZ) in urethane-anesthetized G2R43Q mice and controls in a blinded setting.Compared to wildtype controls in G2R43Q mice after PTZ injection we found 1.) Increased cortical spontaneous activity in layer 2/3 and layer 5/6 pyramidal neurons (increased standard deviation of the mean membrane potential in WC recordings), 2.) Increased variance of stimulus evoked cortical responses in VSDI experiments. 3.) The cortical effects are not due to increased strength or precision of thalamic output. In summary our findings support the hypothesis of a cortical pathology in this mouse model of human genetic absence epilepsy. Further study is needed to characterize underlying molecular mechanisms.