Inappropriate Neural Activity during a Sensitive Period in Embryogenesis Results in Persistent Seizure-like Behavior.
Inappropriate Neural Activity during a Sensitive Period in Embryogenesis Results in Persistent Seizure-like Behavior.
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DOI：
10.1016/j.cub.2015.09.040
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发表时间：
2015-11-16
期刊：
影响因子：
--
通讯作者：
Baines RA
中科院分区：
文献类型：
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作者：
Giachello CN;Baines RA
神经回路的成熟需要依赖活动的过程，这些过程为成人适当行为的出现奠定了基础。有人提出，在这些事件发挥最大影响的特定关键时期，这些事件的干扰可能会导致神经发育疾病，包括癫痫。然而，神经回路的复杂性，加上缺乏关于哺乳动物网络形成的信息，使得直接研究这一假说变得困难。另一种模型，包括果蝇黑腹果蝇，显示出实验性癫痫样活动和临床表型之间的显著相似之处。特别是，一组被称为bang敏感(Bs)突变体的苍蝇已被广泛用于研究癫痫发作的病理生理机制。幼虫阶段的癫痫表型可以用电击试验来测量，在摄入典型的抗癫痫药物(AEDs)后，bs突变体的这种行为显著减少。在这项研究中，我们描述了果蝇胚胎发育的一个关键期，在此期间，对神经活动的操纵足以显着影响胚胎后阶段的癫痫行为。我们表明，在关键时期抑制升高的活动足以抑制癫痫发作，这是BS癫痫模型的特征。相比之下，在同一时期，在野生型(WT)中增加神经元兴奋足以永久地诱导癫痫行为。此外，我们还表明，WT癫痫的诱导与运动神经元输入的功能改变有关，这是bs突变体的一个特征。AEDs的先期给药挽救了癫痫的诱发，为遗传性癫痫的早期药物干预开辟了一个新的视角。活动操纵为回路功能定义了一个临界期，在此关键期内异常活动诱发癫痫发作，早期药物干预阻止了胚胎后阶段癫痫的发生，癫痫行为与运动神经元突触的异常兴奋相关，Giachello和Baines表明，在癫痫的遗传学和化学模型中，阻止果蝇胚胎发育关键期的神经元异常活动足以防止癫痫行为的出现。
Maturation of neural circuits requires activity-dependent processes that underpin the emergence of appropriate behavior in the adult. It has been proposed that disruption of these events, during specific critical periods when they exert maximal influence, may lead to neurodevelopmental diseases, including epilepsy. However, complexity of neurocircuitry, coupled with the lack of information on network formation in mammals, makes it difficult to directly investigate this hypothesis. Alternative models, including the fruit fly Drosophila melanogaster, show remarkable similarities between experimental seizure-like activity and clinical phenotypes. In particular, a group of flies, termed bang-sensitive (bs) mutants have been extensively used to investigate the pathophysiological mechanisms underlying seizure. Seizure phenotype can be measured in larval stages using an electroshock assay, and this behavior in bs mutants is dramatically reduced following ingestion of typical anti-epileptic drugs (AEDs). In this study we describe a critical period of embryonic development in Drosophila during which manipulation of neural activity is sufficient to significantly influence seizure behavior at postembryonic stages. We show that inhibition of elevated activity, characteristic of bs seizure models, during the critical period is sufficient to suppress seizure. By contrast, increasing neuronal excitation during the same period in wild-type (WT) is sufficient to permanently induce a seizure behavior. Further, we show that induction of seizure in WT correlates with functional alteration of motoneuron inputs that is a characteristic of bs mutants. Induction of seizure is rescued by prior administration of AEDs, opening a new perspective for early drug intervention in the treatment of genetic epilepsy. Activity manipulation defines a critical period for circuit functionality Abnormal activity during the critical period induces seizure Early drug intervention prevents seizure occurrence at postembryonic stages Seizure behavior correlates with aberrant synaptic excitation of motoneurons Giachello and Baines show that preventing abnormal neuronal activity during a critical period of Drosophila embryogenesis in genetic and chemical models of seizure is sufficient to prevent the emergence of seizure behavior.