Multiple lines of evidence implicate dysregulated microglia-mediated synaptic pruning in the pathophysiology of schizophrenia. In vitro human cellular studies represent a promising means of pursuing this hypothesis, complementing efforts with animal models and postmortem human data while addressing their limitations. The challenges in culturing homogeneous populations of cells derived from postmortem or surgical biopsy brain material from patients, and their limited availability, has led to a focus on differentiation of induced pluripotent stem cells. These methods too have limitations, in that they disrupt the epigenome and can demonstrate line-to-line variability due in part to extended time in culture, partial reprogramming, and/or residual epigenetic memory from the cell source, yielding large technical artifacts. Yet another strategy uses direct transdifferentiation of peripheral mononuclear blood cells, or umbilical cord blood cells, to microglia-like cells. Any of these approaches can be paired with patient-derived synaptosomes from differentiated neurons as a simpler alternative to co-culture. Patient-derived microglia models may facilitate identification of novel modulators of synaptic pruning and identification of biomarkers that may allow more targeted early interventions.

多种证据表明小胶质细胞介导的突触修剪失调在精神分裂症的病理生理学中。体外人类细胞研究代表了实现这一假设的一种有前途的方法，用动物模型和死后人类数据补充了努力，同时解决了它们的局限性。培养来自患者死后或手术活检脑材料的同质细胞群面临的挑战及其有限的可用性，导致人们将注意力集中在诱导多能干细胞的分化上。这些方法也有局限性，因为它们破坏了表观基因组，并且可以证明系与系之间的变异性，部分原因是培养时间延长、部分重编程和/或来自细胞源的残留表观遗传记忆，从而产生大量的技术工件。另一种策略是使用外周单核血细胞或脐带血细胞直接转分化为小胶质细胞样细胞。这些方法中的任何一种都可以与来自分化神经元的患者来源的突触体配对，作为共培养的更简单的替代方案。患者来源的小胶质细胞模型可能有助于识别突触修剪的新型调节剂和生物标志物的识别，从而可以进行更有针对性的早期干预。