Abstract：
Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.
摘要：
对抗小脑共济失调的特定药物，一组以行走困难为特征的使人衰弱的运动障碍，平衡与协调，仍然缺乏。值得注意的是,小脑小胶质细胞活化似乎是不同类型共济失调患者和啮齿动物模型的共同特征。然而,目前尚缺乏体内小脑小胶质细胞活化足以诱导共济失调的直接证据。这里,通过采用化学遗传学方法选择性地和直接地操纵小脑小胶质细胞，我们发现，小脑疣中小胶质细胞的特定化学遗传激活直接导致野生型小鼠的共济失调症状和3-乙酰吡啶（3-AP）小鼠的共济失调性运动障碍加重，小脑共济失调的经典小鼠模型。机械上,通过化学遗传学M3D（Gq）刺激或3-AP建模过度刺激浦肯野细胞（PC）诱导的小脑小胶质细胞促炎激活，从而引发共济失调。小胶质细胞来源的TNF-α的阻断,最重要的促炎细胞因子之一，减弱由小胶质细胞驱动的PCs多动症。此外，PLX3397和米诺环素对小脑小胶质细胞活化的化学抑制或对小脑小胶质细胞活化的抑制减少了促炎细胞因子的产生，包括TNF-α,有效地恢复PC的过度激活并减轻3-AP小鼠的运动缺陷。这些结果表明，小脑小胶质细胞活化可能会加重神经炎症反应，并随后诱导PCs功能障碍。进而引发共济失调运动缺陷。因此，我们的发现揭示了小脑小胶质细胞的促炎激活和共济失调运动症状之间的因果关系。这可能为通过靶向小胶质细胞和小胶质细胞衍生的炎症介质来治疗小脑共济失调提供新的证据。
