Knock-in mouse model of alternating hemiplegia of childhood: Behavioral and electrophysiologic characterization
Knock-in mouse model of alternating hemiplegia of childhood: Behavioral and electrophysiologic characterization
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DOI：
10.1111/epi.12878
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发表时间：
2015-01-01
期刊：
影响因子：
5.6
通讯作者：
Mikati, Mohamad A.
中科院分区：
文献类型：
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作者：
Hunanyan, Arsen S.;Fainberg, Nina A.;Mikati, Mohamad A.
目的神经元性Na+/K+-ATPase atp13亚单位的突变被认为与癫痫发作、偏瘫和其他儿童交替性偏瘫(AHC)症状有关。然而，ATP1A3突变介导其病理生理后果的机制尚不清楚。对以下假设进行了研究：(1)我们的新型敲入小鼠携带最常见的导致AHC(D801N)的杂合性突变，将表现出人类状况的表现并表现出癫痫的易感性；(2)该小鼠模型的基本病理生理包括对Schaffer侧支的电刺激反应的兴奋性增加和扩散性抑制(SD)的异常易感性。比较两组大鼠的行为测试、杏仁核点燃、氟乙基诱发癫痫阈值、自发性反复癫痫发作(SRS)和其他阵发性活动。在体外海马区进行电生理切片实验，以评估高兴奋性和SD的易感性。结果突变小鼠表现出与人类AHC相似的独特表型。他们有异常的冲动性、记忆力、步态、运动协调性、震颤、运动控制、内源性伤害性反应、阵发性偏瘫、肢体瘫痪、肌张力障碍和SRS，以及对点燃、氟乙基诱发癫痫和意外死亡的易感性。与WT动物相比，突变体的海马片对传送到Schaffer侧支的1赫兹脉冲刺激显示出过度兴奋的反应，并具有明显更长的K+诱导的SD反应持续时间。意义我们的模型再现了人类AHC的主要特征，并表明atp13功能障碍导致异常的短期可塑性，伴随着兴奋性增加(癫痫的潜在机制)和更严重的SD反应的易感性(可能的偏瘫机制)。这种人类状况的模型应该有助于理解这些表型背后的分子途径，并可能导致识别与atp13相关的疾病和癫痫的新治疗策略。
ObjectivesMutations in the ATP13 subunit of the neuronal Na+/K+-ATPase are thought to be responsible for seizures, hemiplegias, and other symptoms of alternating hemiplegia of childhood (AHC). However, the mechanisms through which ATP1A3 mutations mediate their pathophysiologic consequences are not yet understood. The following hypotheses were investigated: (1) Our novel knock-in mouse carrying the most common heterozygous mutation causing AHC (D801N) will exhibit the manifestations of the human condition and display predisposition to seizures; and (2) the underlying pathophysiology in this mouse model involves increased excitability in response to electrical stimulation of Schaffer collaterals and abnormal predisposition to spreading depression (SD).MethodsWe generated the D801N mutant mouse (Mashlool, Mashl(+/-)) and compared mutant and wild-type (WT) littermates. Behavioral tests, amygdala kindling, flurothyl-induced seizure threshold, spontaneous recurrent seizures (SRS), and other paroxysmal activities were compared between groups. In vitro electrophysiologic slice experiments on hippocampus were performed to assess predisposition to hyperexcitability and SD.ResultsMutant mice manifested a distinctive phenotype similar to that of humans with AHC. They had abnormal impulsivity, memory, gait, motor coordination, tremor, motor control, endogenous nociceptive response, paroxysmal hemiplegias, diplegias, dystonias, and SRS, as well as predisposition to kindling, to flurothyl-induced seizures, and to sudden unexpected death. Hippocampal slices of mutants, in contrast to WT animals, showed hyperexcitable responses to 1Hz pulse-trains of electrical stimuli delivered to the Schaffer collaterals and had significantly longer duration of K+-induced SD responses.SignificanceOur model reproduces the major characteristics of human AHC, and indicates that ATP13 dysfunction results in abnormal short-term plasticity with increased excitability (potential mechanism for seizures) and a predisposition to more severe SD responses (potential mechanism for hemiplegias). This model of the human condition should help in understanding the molecular pathways underlying these phenotypes and may lead to identification of novel therapeutic strategies of ATP13 related disorders and seizures.