Price Obot, Antonio Cibelli, Jian Pan, Libor Velíšek, Jana Velíšková, Eliana Scemes
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引用次数: 0
摘要
儿童癫痫与自闭症谱系障碍(ASD)的共病率很高,而癫痫发作的年龄是行为结果的关键决定因素。人们在动物模型中研究了这些并发症之间的相互作用,结果表明,在出生后早期诱导癫痫发作会导致学习和记忆障碍,并在成年后出现类似自闭症的行为。早期癫痫发作(ELS)后兴奋/抑制(谷氨酸/GABA、ATP/腺苷)平衡的改变被认为是导致神经精神和神经发育障碍的生理事件。虽然嘌呤能/腺苷能信号的改变与癫痫发作和 ASD 有关联,但 ATP 释放通道 Pannexin1(Panx1)是否有助于 ELS 诱导的行为变化,目前尚不清楚。为了解决这个问题,我们在转基因小鼠中使用了 ELS-凯尼酸模型,并对 Panx1 进行了全局性和细胞类型特异性缺失,以评估这些通道是否参与了日后出现的行为缺陷。我们的研究表明,ELS 会导致依赖于 Panx1 的社会行为缺陷,并在不涉及 Panx1 的空间记忆测试中表现不佳。这些发现为 ELS 与成年行为缺陷之间的联系提供了支持。此外,我们还发现神经元而非星形胶质细胞的 Panx1 是一个潜在的靶点,可专门限制星形胶质细胞增生和早期癫痫发作导致的社会行为缺陷。
Pannexin1 Mediates Early-Life Seizure-Induced Social Behavior Deficits.
There is a high co-morbidity between childhood epilepsy and autism spectrum disorder (ASD), with age of seizure onset being a critical determinant of behavioral outcomes. The interplay between these comorbidities has been investigated in animal models with results showing that the induction of seizures at early post-natal ages leads to learning and memory deficits and to autistic-like behavior in adulthood. Modifications of the excitation/inhibition (glutamate/GABA, ATP/adenosine) balance that follows early-life seizures (ELS) are thought to be the physiological events that underlie neuropsychiatric and neurodevelopmental disorders. Although alterations in purinergic/adenosinergic signaling have been implicated in seizures and ASD, it is unknown whether the ATP release channels, Pannexin1 (Panx1), contribute to ELS-induced behavior changes. To tackle this question, we used the ELS-kainic acid model in transgenic mice with global and cell type specific deletion of Panx1 to evaluate whether these channels were involved in behavioral deficits that occur later in life. Our studies show that ELS results in Panx1 dependent social behavior deficits and also in poor performance in a spatial memory test that does not involve Panx1. These findings provide support for a link between ELS and adult behavioral deficits. Moreover, we identify neuronal and not astrocyte Panx1 as a potential target to specifically limit astrogliosis and social behavioral deficits resultant from early-life seizures.
期刊介绍:
ASN NEURO is an open access, peer-reviewed journal uniquely positioned to provide investigators with the most recent advances across the breadth of the cellular and molecular neurosciences. The official journal of the American Society for Neurochemistry, ASN NEURO is dedicated to the promotion, support, and facilitation of communication among cellular and molecular neuroscientists of all specializations.