Rescue of neuronal migration deficits in a mouse model of fetal Minamata disease by increasing neuronal Ca2+ spike frequency
Rescue of neuronal migration deficits in a mouse model of fetal Minamata disease by increasing neuronal Ca2+ spike frequency
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DOI：
10.1073/pnas.1120747109
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发表时间：
2012-03-27
影响因子：
11.1
通讯作者：
Komuro, Hitoshi
中科院分区：
文献类型：
--
作者：
Fahrion, Jennifer K.;Komuro, Yutaro;Komuro, Hitoshi
胎儿水俣病 (FMD) 是由于发育过程中接触甲基汞 (MeHg) 引起的，在胎儿水俣病 (FMD) 患者的大脑中，许多神经元发育不良、异位和迷失方向，表明迁移、成熟和生长受到破坏。甲基汞影响大量信号分子，但人们对哪些信号是甲基汞诱导的神经元发育缺陷的主要目标知之甚少。在这项研究中，我们使用 FMD 小鼠模型，研究了甲基汞如何影响出生后早期发育过程中小脑颗粒细胞的迁移。小脑是对甲基汞暴露最敏感的大脑区域之一，在 FMD 患者的大脑中检测到小脑颗粒细胞的严重损失。我们发现，MeHg 通过改变 Ca2+、cAMP 和胰岛素样生长因子 1 (IGF1) 信号传导，降低体细胞 Ca2+ 尖峰的频率，从而抑制颗粒细胞迁移。首先，甲基汞以剂量依赖性方式减慢颗粒细胞迁移的速度，与迁移模式无关。其次，MeHg 以剂量依赖性方式降低颗粒细胞体细胞中自发 Ca2+ 尖峰的频率。第三，独特的体内细胞迁移实时成像系统表明，通过刺激内部Ca2+释放和Ca2+流入、抑制cAMP活性或激活IGF1受体来减少MeHg对体细胞Ca2+尖峰频率的抑制作用，从而改善MeHg对颗粒细胞迁移的抑制作用。这些结果表明，Ca2+ 峰值频率以及 Ca2+、cAMP 和 IGF1 信号传导的改变可能是甲基汞中毒婴儿的潜在治疗靶点。
In the brains of patients with fetal Minamata disease (FMD), which is caused by exposure to methylmercury (MeHg) during development, many neurons are hypoplastic, ectopic, and disoriented, indicating disrupted migration, maturation, and growth. MeHg affects a myriad of signaling molecules, but little is known about which signals are primary targets for MeHg-induced deficits in neuronal development. In this study, using a mouse model of FMD, we examined how MeHg affects the migration of cerebellar granule cells during early postnatal development. The cerebellum is one of the most susceptible brain regions to MeHg exposure, and profound loss of cerebellar granule cells is detected in the brains of patients with FMD. We show that MeHg inhibits granule cell migration by reducing the frequency of somal Ca2+ spikes through alterations in Ca2+, cAMP, and insulin-like growth factor 1 (IGF1) signaling. First, MeHg slows the speed of granule cell migration in a dose-dependent manner, independent of the mode of migration. Second, MeHg reduces the frequency of spontaneous Ca2+ spikes in granule cell somata in a dose-dependent manner. Third, a unique in vivo live-imaging system for cell migration reveals that reducing the inhibitory effects of MeHg on somal Ca2+ spike frequency by stimulating internal Ca2+ release and Ca2+ influxes, inhibiting cAMP activity, or activating IGF1 receptors ameliorates the inhibitory effects of MeHg on granule cell migration. These results suggest that alteration of Ca2+ spike frequency and Ca2+, cAMP, and IGF1 signaling could be potential therapeutic targets for infants with MeHg intoxication.