Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto University Hospital, Shogoin-Kawaramachi-cho, Sakyo-ward, Kyoto 606-8507, Japan.
The Hakubi Center for Advanced Research, Kyoto University, Yoshida, Sakyo-ward, Kyoto 606-8501, Japan; Department of Molecular and Cellular Physiology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ward, Kyoto 606-8501, Japan.
Cell Rep. 2019 Sep 10;28(11):2923-2938.e8. doi: 10.1016/j.celrep.2019.07.078.
Cerebellar dysfunction relates to various psychiatric disorders, including autism spectrum and depressive disorders. However, the physiological aspect is less advanced. Here, we investigate the immune-triggered hyperexcitability in the cerebellum on a wider scope. Activated microglia via exposure to bacterial endotoxin lipopolysaccharide or heat-killed Gram-negative bacteria induce a potentiation of the intrinsic excitability in Purkinje neurons, which is suppressed by microglia-activity inhibitor and microglia depletion. An inflammatory cytokine, tumor necrosis factor alpha (TNF-α), released from microglia via toll-like receptor 4, triggers this plasticity. Our two-photon FRET ATP imaging shows an increase in ATP concentration following endotoxin exposure. Both TNF-α and ATP secretion facilitate synaptic transmission. Region-specific inflammation in the cerebellum in vivo shows depression- and autistic-like behaviors. Furthermore, both TNF-α inhibition and microglia depletion revert such behavioral abnormality. Resting-state functional MRI reveals overconnectivity between the inflamed cerebellum and the prefrontal neocortical regions. Thus, immune activity in the cerebellum induces neuronal hyperexcitability and disruption of psychomotor behaviors in animals.
小脑功能障碍与各种精神疾病有关，包括自闭症谱系和抑郁症。然而，生理方面的研究还不够深入。在这里，我们更广泛地研究了免疫触发小脑过度兴奋的问题。通过暴露于细菌内毒素脂多糖或热灭活革兰氏阴性菌激活小胶质细胞，会导致浦肯野神经元的内在兴奋性增强，而小胶质细胞活性抑制剂和小胶质细胞耗竭会抑制这种增强。小胶质细胞通过 Toll 样受体 4 释放的炎症细胞因子肿瘤坏死因子 α (TNF-α)触发这种可塑性。我们的双光子 FRET ATP 成像显示，内毒素暴露后 ATP 浓度增加。TNF-α和 ATP 的分泌都促进了突触传递。体内小脑的区域特异性炎症表现出抑郁和自闭症样行为。此外，TNF-α抑制和小胶质细胞耗竭都可以逆转这种行为异常。静息态功能磁共振成像显示，炎症小脑与前额叶新皮层区域之间存在过度连接。因此，小脑的免疫活性会导致神经元过度兴奋，并破坏动物的精神运动行为。
