Institute of Anatomy, Anatomy and Cell Biology, University of Bonn, Nussallee 10, 53125, Bonn, Germany.
National Reference Laboratory for Tuberculosis, ICMR-RMRC, Bhubaneswar, Odisha, India.
J Neuroinflammation. 2024 Nov 28;21(1):306. doi: 10.1186/s12974-024-03301-6.
Autism spectrum disorders (ASD) have a complex pathogenesis thought to include both genetic and extrinsic factors. Among the latter, inflammation of the developing brain has recently gained growing attention. However, how genetic predisposition and inflammation might converge to precipitate autistic behavior remains elusive. Cerebellar structure and function are well known to be affected in autism. We therefore used cerebellar slice cultures to probe whether inflammatory stimulation and (over)expression of the autism susceptibility gene Engrailed-2 interact in shaping differentiation of Purkinje cells, key organizers of cerebellar histogenesis and function. We show that lipopolysaccharide treatment reduces Purkinje cell dendritogenesis and that this effect is enhanced by over-expression of Engrailed-2 in these cells. The effects of lipopolysaccharide can be blocked by inhibiting microglia proliferation and also by blocking tumor necrosis factor alpha receptor signaling, suggesting microglia and tumor necrosis factor alpha are major players in this scenario. These findings identify Purkinje cells as a potential integrator of genetic and environmental signals that lead to an autism-associated morphology.
自闭症谱系障碍（ASD）的发病机制复杂，既有遗传因素也有外在因素。在后者中，发育中大脑的炎症最近受到越来越多的关注。然而，遗传易感性和炎症如何汇聚导致自闭症行为仍然难以捉摸。小脑的结构和功能在自闭症中众所周知会受到影响。因此，我们使用小脑切片培养物来探究炎症刺激和自闭症易感基因 Engrailed-2 的（过）表达是否相互作用，以塑造浦肯野细胞的分化，浦肯野细胞是小脑组织发生和功能的关键组织者。我们表明，脂多糖处理会减少浦肯野细胞树突生成，而这些细胞中 Engrailed-2 的过表达会增强这种作用。脂多糖的作用可以通过抑制小胶质细胞增殖和阻断肿瘤坏死因子 alpha 受体信号转导来阻断，这表明小胶质细胞和肿瘤坏死因子 alpha 是这种情况下的主要参与者。这些发现确定浦肯野细胞是导致自闭症相关形态的遗传和环境信号的潜在整合者。
