Autism is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors. Genetic screening has identified synaptic, transcriptional, and chromatin genes disrupted in autistic patients. Haploinsufficiency of Shank3, which encodes a scaffold protein at glutamatergic synapses, is causally linked to autism. Using a Shank3-deficient mouse model that exhibits prominent autism-like phenotypes, we have found that histone acetylation in the prefrontal cortex (PFC) is abnormally low, which can be reversed by MS-275 (also known as Entinostat, SNDX-275), a class I histone deacetylase (HDAC) inhibitor that is selectively potent in PFC. A brief (3-day) treatment with MS-275 (i.p.) led to the sustained (11 days) rescue of autistic social preference deficits in Shank3-deficient mice, without altering locomotion, motor coordination, anxiety, or the increased grooming. MS-275 treatment also rescued the diminished NMDAR surface expression and NMDAR function induced by Shank3 deficiency. Moreover, F-actin at synapses was restored and the transcription of actin regulators was elevated by MS-275 treatment of Shank3-deficient mice, which may contribute to the recovery of actin-based NMDAR synaptic delivery. Taken together, these results suggest that MS-275 treatment could normalize the aberrant epigenetic regulation of genes, leading to the amelioration of synaptic and social deficits associated with autism.

中文翻译：

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组蛋白脱乙酰基酶抑制剂MS-275在Shank3缺陷型自闭症小鼠模型中恢复社交和突触功能。

自闭症是一种以社交缺陷和重复行为为特征的神经发育障碍。遗传筛选已鉴定出在自闭症患者中被破坏的突触，转录和染色质基因。在谷氨酸能突触中编码支架蛋白的Shank3的单倍功能不足与自闭症有因果关系。使用表现出明显的自闭症样表型的Shank3缺陷小鼠模型，我们发现前额叶皮层（PFC）中的组蛋白乙酰化异常低，可以被MS-275（也称为Entinostat，SNDX-275）逆转，是一种I类组蛋白脱乙酰基酶（HDAC）抑制剂，在PFC中具有选择性。用MS-275（ip）进行的短暂（3天）治疗可以持续（11天）挽救Shank3缺陷小鼠的自闭症社会偏好缺陷，而不会改变运动，运动协调，焦虑，或增加修饰。MS-275治疗还挽救了Shank3缺乏症诱导的NMDAR表面表达和NMDAR功能降低。此外，通过Shank3缺陷小鼠的MS-275治疗，突触中的F-肌动蛋白得以恢复，肌动蛋白调节剂的转录得以提高，这可能有助于恢复基于肌动蛋白的NMDAR突触传递。综上所述，这些结果表明，MS-275治疗可以使异常的表观遗传调控基因正常化，从而改善与自闭症相关的突触和社交缺陷。通过MS-275治疗Shank3缺陷小鼠，突触中的F-肌动蛋白得以恢复，肌动蛋白调节剂的转录得以提高，这可能有助于恢复基于肌动蛋白的NMDAR突触传递。综上所述，这些结果表明，MS-275治疗可以使异常的表观遗传调控基因正常化，从而改善与自闭症相关的突触和社交缺陷。通过MS-275治疗Shank3缺陷小鼠，突触中的F-肌动蛋白得以恢复，肌动蛋白调节剂的转录得以提高，这可能有助于恢复基于肌动蛋白的NMDAR突触传递。综上所述，这些结果表明，MS-275治疗可以使异常的表观遗传调控基因正常化，从而改善与自闭症相关的突触和社交缺陷。