Yang Dongren, Kim Kyung Ho, Phimister Andrew, Bachstetter Adam D, Ward Thomas R, Stackman Robert W, Mervis Ronald F, Wisniewski Amy B, Klein Sabra L, Kodavanti Prasada Rao S, Anderson Kim A, Wayman Gary, Pessah Isaac N, Lein Pamela J
Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, Oregon, USA.
Environ Health Perspect. 2009 Mar;117(3):426-35. doi: 10.1289/ehp.11771. Epub 2008 Sep 12.
Neurodevelopmental disorders are associated with altered patterns of neuronal connectivity. A critical determinant of neuronal connectivity is the dendritic morphology of individual neurons, which is shaped by experience. The identification of environmental exposures that interfere with dendritic growth and plasticity may, therefore, provide insight into environmental risk factors for neurodevelopmental disorders.
We tested the hypothesis that polychlorinated biphenyls (PCBs) alter dendritic growth and/or plasticity by promoting the activity of ryanodine receptors (RyRs).
The Morris water maze was used to induce experience-dependent neural plasticity in weanling rats exposed to either vehicle or Aroclor 1254 (A1254) in the maternal diet throughout gestation and lactation. Developmental A1254 exposure promoted dendritic growth in cerebellar Purkinje cells and neocortical pyramidal neurons among untrained animals but attenuated or reversed experience-dependent dendritic growth among maze-trained littermates. These structural changes coincided with subtle deficits in spatial learning and memory, increased [3H]-ryanodine binding sites and RyR expression in the cerebellum of untrained animals, and inhibition of training-induced RyR upregulation. A congener with potent RyR activity, PCB95, but not a congener with negligible RyR activity, PCB66, promoted dendritic growth in primary cortical neuron cultures and this effect was blocked by pharmacologic antagonism of RyR activity.
Developmental exposure to PCBs interferes with normal patterns of dendritic growth and plasticity, and these effects may be linked to changes in RyR expression and function. These findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling.
神经发育障碍与神经元连接模式的改变有关。神经元连接的一个关键决定因素是单个神经元的树突形态，其受经验塑造。因此，识别干扰树突生长和可塑性的环境暴露因素，可能有助于深入了解神经发育障碍的环境风险因素。
我们检验了多氯联苯（PCBs）通过促进兰尼碱受体（RyRs）的活性来改变树突生长和/或可塑性的假说。
在整个妊娠期和哺乳期，给母鼠喂食溶剂或Aroclor 1254（A1254），利用莫里斯水迷宫诱导断奶大鼠产生经验依赖性神经可塑性。发育期暴露于A1254可促进未训练动物小脑浦肯野细胞和新皮质锥体神经元的树突生长，但会减弱或逆转迷宫训练同窝幼崽的经验依赖性树突生长。这些结构变化与空间学习和记忆的细微缺陷、未训练动物小脑中[3H]-兰尼碱结合位点和RyR表达的增加以及训练诱导的RyR上调的抑制相一致。具有强大RyR活性的同系物PCB95可促进原代皮质神经元培养物中的树突生长，而具有可忽略不计的RyR活性的同系物PCB66则不能，且这种作用可被RyR活性的药理学拮抗作用阻断。
发育期暴露于PCBs会干扰树突生长和可塑性的正常模式，这些影响可能与RyR表达和功能的变化有关。这些发现确定PCBs为神经发育障碍的候选环境风险因素，尤其是在钙信号传导存在遗传缺陷的儿童中。
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