Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons
Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons
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DOI：
10.1073/pnas.1514962112
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发表时间：
2015-11-03
影响因子：
11.1
通讯作者：
Galve-Roperh, Ismael
中科院分区：
文献类型：
--
作者：
de Salas-Quiroga, Adan;Diaz-Alonso, Javier;Galve-Roperh, Ismael
CB1 大麻素受体是 Delta(9)-四氢大麻酚 (THC) 的主要靶标，THC 是大麻中最重要的精神活性化合物，它在大脑发育中发挥着至关重要的调节作用，动物模型中操纵其对神经发育的影响就证明了这一点。同样，怀孕期间使用娱乐性大麻会影响后代的大脑结构和功能。然而，产前 THC 暴露后果的确切神经生物学底物仍然未知。由于 CB1 信号传导已知可调节远距离皮质连接，因此我们分析了 THC 暴露对皮质投射神经元发育的影响。在有限的时间窗口内对怀孕小鼠施用 THC 会干扰大脑下投射神经元的生成，从而改变皮质脊髓的连接性，并对成年后代的精细运动性能产生持久的改变。 THC 暴露的后果让人想起 CB1 受体基因消除引起的后果，并且 CB1 缺失小鼠对 THC 诱导的改变具有抵抗力。胚胎 THC 神经元靶标的身份是通过 Cre 介导的、谱系特异性的、CB1 表达拯救策略在 CB1 无效背景下确定的。背侧端脑谷氨酸能神经元而非前脑 GABA 能神经元中的早期选择性 CB1 重新表达挽救了 CB1 缺失小鼠皮质脊髓运动神经元发育缺陷，并恢复了对 THC 诱导的运动改变的易感性。此外，THC 给药还会导致癫痫易感性增加，这是通过干扰 CB1 依赖性谷氨酸能和 GABA 能神经元发育调节而介导的。这些发现表明，产前接触 THC 对成年后代会产生长期的有害后果，这完全是由于 THC 破坏 CB1 信号传导的神经发育作用的能力所介导的。
The CB1 cannabinoid receptor, the main target of Delta(9)-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling.