Dim light exposure of the mother during pregnancy has been proposed as one of the environmental factors that affect the fetal brain development in schizophrenia. Melatonin circulating levels are regulated by the environmental light/dark cycle. This hormone stimulates neuronal differentiation in the adult brain. However, little is known about its role in the fetal human brain development. Olfactory neuronal precursors (ONPs) are useful for studying the physiopathology of neuropsychiatric diseases because they mimic all the stages of neurodevelopment in culture. Here, we first characterized whether melatonin stimulates neuronal differentiation in cloned ONPs obtained from a healthy control subject (HCS). Then, melatonin effects were evaluated in primary cultures of ONPs derived from a patient diagnosed with schizophrenia (SZ) and an age‐ and gender‐matched HCS. Axonal formation was evidenced morphologically by tau immunostaining and by GSK3β phosphorylated state. Potassium‐evoked secretion was assessed as a functional feature of differentiated neurons. As well, we report the expression of MT1/2 receptors in human ONPs for the first time. Melatonin stimulated axonal formation and ramification in cloned ONPs through a receptor‐mediated mechanism and enhanced the amount and velocity of axonal and somatic secretion. SZ ONPs displayed reduced axogenesis associated with lower levels of pGSK3β and less expression of melatonergic receptors regarding the HCS ONPs. Melatonin counteracted this reduction in SZ cells. Altogether, our results show that melatonin signaling is crucial for functional differentiation of human ONPs, strongly suggesting that a deficit of this indoleamine may lead to an impaired neurodevelopment which has been associated with the etiology of schizophrenia.

中文翻译：

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褪黑素在精神分裂症神经发育病因中的作用：人类嗅觉神经元前体的研究

已经提出，母亲在怀孕期间的昏暗曝光是影响精神分裂症胎儿大脑发育的环境因素之一。褪黑激素的循环水平受环境明暗循环的调节。这种激素刺激成年大脑中的神经元分化。然而，关于它在胎儿人脑发育中的作用知之甚少。嗅觉神经元前体（ONPs）可用于研究神经精神疾病的生理病理学，因为它们模拟了文化中神经发育的所有阶段。在这里，我们首先表征褪黑素是否刺激从健康对照对象（HCS）获得的克隆ONP中的神经元分化。然后，在诊断为精神分裂症（SZ）和年龄和性别匹配的HCS的患者的ONP的原代培养中评估了褪黑激素的作用。通过tau免疫染色和GSK3β磷酸化状态在形态学上证实了轴突的形成。钾诱发的分泌被评估为分化神经元的功能特征。同样，我们首次报道了MT1 / 2受体在人ONP中的表达。褪黑素通过受体介导的机制刺激克隆的ONP中的轴突形成和分支，并增强了轴突和体液分泌的数量和速度。就HCS ONP而言，SZ ONP显示出与较低水平的pGSK3β相关的轴突生成减少和褪黑素受体的表达较少。褪黑素抵消了SZ细胞的这种减少。共，