Disease, injury and aging induce pathological reactive astrocyte states that contribute to neurodegeneration. Modulating reactive astrocytes therefore represent an attractive therapeutic strategy. Here we describe the development of an astrocyte phenotypic screening platform for identifying chemical modulators of astrocyte reactivity. Leveraging this platform for chemical screening, we identify histone deacetylase 3 (HDAC3) inhibitors as effective suppressors of pathological astrocyte reactivity. We demonstrate that HDAC3 inhibition reduces molecular and functional characteristics of reactive astrocytes in vitro. Transcriptional and chromatin mapping studies show that HDAC3 inhibition disarms pathological astrocyte gene expression and function while promoting the expression of genes associated with beneficial astrocytes. Administration of RGFP966, a small molecule HDAC3 inhibitor, blocks reactive astrocyte formation and promotes neuroprotection in vivo in mice. Collectively, these results establish a platform for discovering modulators of reactive astrocyte states, inform the mechanisms that control astrocyte reactivity and demonstrate the therapeutic benefits of modulating astrocyte reactivity for neurodegenerative diseases.

疾病、损伤和衰老会诱发导致神经变性的病理反应性星形胶质细胞状态。因此，调节反应性星形胶质细胞代表了一种有吸引力的治疗策略。在这里，我们描述了用于识别星形胶质细胞反应性化学调节剂的星形胶质细胞表型筛选平台的开发。利用该平台进行化学筛选，我们确定组蛋白脱乙酰酶 3 (HDAC3) 抑制剂是病理性星形胶质细胞反应性的有效抑制剂。我们证明 HDAC3 抑制会降低体外反应性星形胶质细胞的分子和功能特征。转录和染色质图谱研究表明，HDAC3 抑制可解除病理性星形胶质细胞基因表达和功能，同时促进与有益星形胶质细胞相关的基因表达。 RGFP966（一种小分子 HDAC3 抑制剂）的给药可阻断反应性星形胶质细胞的形成并促进小鼠体内的神经保护。总的来说，这些结果建立了一个发现反应性星形胶质细胞状态调节剂的平台，为控制星形胶质细胞反应性的机制提供信息，并证明调节星形胶质细胞反应性对神经退行性疾病的治疗益处。