Science2014-06-12 3:12 PM

降低氯离子可恢复转换功能 Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring

Abstract 

We report that the oxytocin-mediated neuroprotective γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.

论文摘要 

据一则新的报告显示,一种药物可防止自闭症模型的怀孕小鼠的后代出现自闭症行为,虽然无法在产前将该药物给予人类孕妇(因为没有办法筛检人类胎儿的自闭症),但在之后的发育过程中给予该药物,即将这种药物给予已经出现自闭症症状的幼童,这样临床试验正在取得进展。自闭症谱系障碍或ASD的成因是复杂的。脑神经元长期的兴奋似乎是其部分肇因。因此,GABA——它是大脑中主要的抑制性神经递质——受到了关注;对一个生长中的胎儿而言,GABA通常会激发其大脑内神经元并接着在其出生时让这些神经元平静下来,这一转换是来自母体的催产素介导的,它具有保护性的功效。但在自闭症中,这一转换没有发生。其神经元处于激发状态,因为氯离子——这是一种关键的信号传导分子——的积聚浓度要高于其应有的浓度在先前提到的临床试验中,一种叫作布美他尼的可降低氯离子的药物似乎能够在有ASD的儿童中恢复GABA的转换功能,同时减少自闭症和阿斯伯格综合征的严重程度。为了更好地理解布美他尼是否会以他们认为的作用方式影响(即通过降低氯离子的水平)作为GABA转换基础的细胞过程,并确定仅恢复该转换本身是否就能减轻自闭症的症状,RomanTyzio及其同事(他们中有数人参与了临床试验)对两个啮齿类的自闭症动物模型进行了研究。研究人员发现,在妊娠小鼠中的产素没有从母体向胎儿发送信号,而其结果是氯离子会在胎儿神经元内积聚,其浓度比应有的浓度要高。然而,通过给母体注射布美他尼,研究人员能够将氯离子浓度降至其恰当的浓度,并因而恢复了GABA的转换功能。至关重要的是,接触这种治疗的小鼠后代没有显现自闭症的特征。这项研究为在那些正在参与临床实验的并已经出现了自闭症症状的幼童使用布美他尼提供了支持。

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