SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice
SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice
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DOI：
10.1101/2021.01.24.427868
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发表时间：
2021-01
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通讯作者：
Kan Yang;Yuhan Shi;Xiujuan Du;Jincheng Wang;Yue-fang Zhang;Shifang Shan;Yiting Yuan;Ruoqing Wang-Ruoqin
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作者：
Kan Yang;Yuhan Shi;Xiujuan Du;Jincheng Wang;Yue-fang Zhang;Shifang Shan;Yiting Yuan;Ruoqing Wang-Ruoqin
自闭症谱系障碍（Autism spectrum disorder，ASD）是一种高度遗传的神经发育障碍，其核心症状是社会交往障碍和明显的重复行为。虽然约50- 70%的ASD患者患有智力残疾（ID）或发育迟缓（DD）的合并症，但也有一些ASD患者仅表现出核心症状，但没有ID/DD，这就提出了一个问题，即是否存在ASD核心症状特异性的遗传成分和神经回路。在这里，通过关注未显示化合物ID或DD的ASD患者，我们确定了编码小泛素样修饰物（SUMO）解偶联酶的Sentrin特异性肽酶1（SENP 1）基因的从头杂合基因截短突变，作为ASD的潜在新候选基因。我们发现，Senp 1单倍型不足的小鼠表现出自闭症的核心症状，如社交互动和重复行为的缺陷，但学习和记忆能力正常。此外，我们发现，抑制性和兴奋性突触功能受到严重影响，在后压无颗粒（RSA）皮质的Senp 1单倍不足的小鼠。Senp 1的缺乏导致脆性X智力低下蛋白（FMRP）蛋白的SUMO化和降解，该蛋白由FMR 1基因编码，也与ASD综合征有关。重要的是，在RSA中重新引入SENP 1或FMRP完全挽救了Senp 1单倍不足小鼠的突触功能缺陷和核心自闭症样症状。总之，这些结果表明，RSA中SENP 1-FMRP调节轴的破坏可能导致核心自闭症症状，这为通过神经调节方法进行潜在的治疗干预提供了ASD的候选脑区域。
Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, in which core symptoms are defects of social interaction and evidently repetitive behaviors. Although around 50-70 % of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), there are some ASD patients who exhibit only core symptoms but without ID/DD, raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic ASD. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Together, these results demonstrated that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which provide a candidate brain region of ASD for potential therapeutic intervene by neural modulation approaches.