Endocannabinoids regulate different aspects of neurodevelopment. In utero exposure to the exogenous psychoactive cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC), has been linked with abnormal cortical development in animal models. However, much less is known about the actions of endocannabinoids in human neurons. Here we investigated the effect of the endocannabinoid 2-arachidonoyl glycerol (2AG) and Δ9-THC on the development of neuronal morphology and activation of signaling kinases, in cortical neurons derived from human induced pluripotent stem cells (hiPSCs). Our data indicate that the cannabinoid type 1 receptor (CB1R), but not the cannabinoid 2 receptor (CB2R), GPR55 or TRPV1 receptors, is expressed in young, immature hiPSC-derived cortical neurons. Consistent with previous reports, 2AG and Δ9-THC negatively regulated neurite outgrowth. Interestingly, acute exposure to both 2AG and Δ9-THC inhibited phosphorylation of serine/threonine kinase extracellular signal-regulated protein kinases (ERK1/2), whereas Δ9-THC also reduced phosphorylation of Akt (aka PKB). Moreover, the CB1R inverse agonist SR 141716A attenuated the decrease in neurite outgrowth and ERK1/2 phosphorylation induced by 2AG and Δ9-THC. Taken together, our data suggest that hiPSC-derived cortical neurons express CB1Rs and are responsive to exogenous cannabinoids. Thus, hiPSC-neurons may represent a good cellular model for investigating the role of the endocannabinoid system in regulating cellular processes in developing human neurons.

中文翻译：

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Δ9-四氢大麻酚和2-AG减少了神经突向外生长，并差异性影响hiPSC来源的皮层神经元的ERK1 / 2和Akt信号传导。

内源性大麻素调节神经发育的不同方面。子宫内暴露于外源性精神活性大麻素Δ9-四氢大麻酚（Δ9-THC）与动物模型中皮质发育异常有关。但是，关于内源性大麻素在人类神经元中的作用的了解还很少。在这里，我们研究了人源性多能干细胞（hiPSC）皮质神经元中内源性大麻素2-花生四烯酰基甘油（2AG）和Δ9-THC对神经元形态发育和信号激酶激活的影响。我们的数据表明，大麻素1型受体（CB1R）而非大麻素2受体（CB2R），GPR55或TRPV1受体在年轻的，未成熟的hiPSC来源的皮质神经元中表达。与先前的报道一致，2AG和Δ9-THC负调控神经突的生长。有趣的是，急性暴露于2AG和Δ9-THC都抑制了丝氨酸/苏氨酸激酶胞外信号调节蛋白激酶（ERK1 / 2）的磷酸化，而Δ9-THC也降低了Akt的磷酸化（aka PKB）。此外，CB1R反向激动剂SR 141716A减弱了2AG和Δ9-THC诱导的神经突增生和ERK1 / 2磷酸化的降低。两者合计，我们的数据表明，hiPSC衍生的皮质神经元表达CB1Rs，并对外源性大麻素有反应。因此，hiPSC神经元可能代表一个很好的细胞模型，用于研究内源性大麻素系统在调节人类神经元发育过程中的作用。而Δ9-THC也减少了Akt（aka PKB）的磷酸化。此外，CB1R反向激动剂SR 141716A减弱了2AG和Δ9-THC诱导的神经突增生和ERK1 / 2磷酸化的降低。两者合计，我们的数据表明，hiPSC衍生的皮质神经元表达CB1Rs，并对外源性大麻素有反应。因此，hiPSC神经元可能代表一个良好的细胞模型，用于研究内源性大麻素系统在调节人类神经元发育过程中的作用。而Δ9-THC也减少了Akt（aka PKB）的磷酸化。此外，CB1R反向激动剂SR 141716A减弱了2AG和Δ9-THC诱导的神经突增生和ERK1 / 2磷酸化的降低。两者合计，我们的数据表明，hiPSC来源的皮质神经元表达CB1Rs，并对外源性大麻素有反应。因此，hiPSC神经元可能代表一个很好的细胞模型，用于研究内源性大麻素系统在调节人类神经元发育过程中的作用。