Schizophrenia (SCZ) and bipolar disorder (BIP) are severe mental disorders with a considerable disease burden worldwide due to early age of onset, chronicity, and lack of efficient treatments or prevention strategies. Whilst our current knowledge is that SCZ and BIP are highly heritable and share common pathophysiological mechanisms associated with cellular signaling, neurotransmission, energy metabolism, and neuroinflammation, the development of novel therapies has been hampered by the unavailability of appropriate models to identify novel targetable pathomechanisms. Recent data suggest that neuron–glia interactions are disturbed in SCZ and BIP, and are modulated by estrogen (E2). However, most of the knowledge we have so far on the neuromodulatory effects of E2 came from studies on animal models and human cell lines, and may not accurately reflect many processes occurring exclusively in the human brain. Thus, here we highlight the advantages of using induced pluripotent stem cell (iPSC) models to revisit studies of mechanisms underlying beneficial effects of E2 in human brain cells. A better understanding of these mechanisms opens the opportunity to identify putative targets of novel therapeutic agents for SCZ and BIP. In this review, we first summarize the literature on the molecular mechanisms involved in SCZ and BIP pathology and the beneficial effects of E2 on neuron–glia interactions. Then, we briefly present the most recent developments in the iPSC field, emphasizing the potential of using patient-derived iPSCs as more relevant models to study the effects of E2 on neuron–glia interactions.

中文翻译：

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使用 iPSC 模型了解雌激素在精神分裂症和双相情感障碍神经元-胶质细胞相互作用中的作用

精神分裂症（SCZ）和双相情感障碍（BIP）是严重的精神障碍，由于发病年龄早、慢性且缺乏有效的治疗或预防策略，在全世界范围内造成相当大的疾病负担。虽然我们目前的知识是 SCZ 和 BIP 具有高度遗传性，并且具有与细胞信号传导、神经传递、能量代谢和神经炎症相关的共同病理生理机制，但由于缺乏适当的模型来识别新的可靶向病理机制，新疗法的开发受到阻碍。最近的数据表明，SCZ 和 BIP 中神经元-胶质细胞的相互作用受到干扰，并受到雌激素 (E2) 的调节。然而，迄今为止我们对 E2 神经调节作用的大部分了解都来自对动物模型和人类细胞系的研究，可能无法准确反映仅发生在人脑中的许多过程。因此，在这里我们强调使用诱导多能干细胞 (iPSC) 模型来重新研究 E2 对人脑细胞有益作用的机制的优势。更好地了解这些机制为确定 SCZ 和 BIP 新型治疗剂的假定靶点提供了机会。在这篇综述中，我们首先总结了有关 SCZ 和 BIP 病理学分子机制以及 E2 对神经元-胶质细胞相互作用的有益影响的文献。然后，我们简要介绍了 iPSC 领域的最新进展，强调使用患者来源的 iPSC 作为更相关的模型来研究 E2 对神经元-胶质细胞相互作用的影响的潜力。