Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with short- and long-term neurological complications. The variety of symptoms makes it difficult to unravel molecular mechanisms underlying neurological sequalae after coronavirus disease 2019 (COVID-19). Here we show that SARS-CoV-2 triggers the up-regulation of synaptic components and perturbs local electrical field potential. Using cerebral organoids, organotypic culture of human brain explants from individuals without COVID-19 and post-mortem brain samples from individuals with COVID-19, we find that neural cells are permissive to SARS-CoV-2 to a low extent. SARS-CoV-2 induces aberrant presynaptic morphology and increases expression of the synaptic components Bassoon, latrophilin-3 (LPHN3) and fibronectin leucine-rich transmembrane protein-3 (FLRT3). Furthermore, we find that LPHN3-agonist treatment with Stachel partially restored organoid electrical activity and reverted SARS-CoV-2-induced aberrant presynaptic morphology. Finally, we observe accumulation of relatively static virions at LPHN3–FLRT3 synapses, suggesting that local hindrance can contribute to synaptic perturbations. Together, our study provides molecular insights into SARS-CoV-2–brain interactions, which may contribute to COVID-19-related neurological disorders.

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染与短期和长期神经系统并发症相关。症状多种多样，因此很难阐明 2019 年冠状病毒病 (COVID-19) 后神经系统后遗症的分子机制。在这里，我们表明 SARS-CoV-2 会触发突触成分的上调并扰乱局部电场电位。使用脑类器官、未感染 COVID-19 的个体的人脑外植体的器官型培养物以及患有 COVID-19 的个体的死后脑样本，我们发现神经细胞对 SARS-CoV-2 的耐受程度较低。 SARS-CoV-2 诱导异常的突触前形态，并增加突触成分巴松管、latrophilin-3 (LPHN3) 和纤连蛋白富含亮氨酸跨膜蛋白 3 (FLRT3) 的表达。此外，我们发现用 Stachel 治疗 LPHN3 激动剂可部分恢复类器官电活动并恢复 SARS-CoV-2 诱导的异常突触前形态。最后，我们观察到 LPHN3-FLRT3 突触处相对静态的病毒体积累，表明局部阻碍可能导致突触扰动。总之，我们的研究提供了对 SARS-CoV-2 与大脑相互作用的分子见解，这可能导致与 COVID-19 相关的神经系统疾病。