Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith-Magenis syndrome.
Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith-Magenis syndrome.
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DOI：
10.1073/pnas.1806796115
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发表时间：
2018-10-16
影响因子：
11.1
通讯作者：
Luo L
中科院分区：
文献类型：
--
作者：
Huang WH;Wang DC;Allen WE;Klope M;Hu H;Shamloo M;Luo L
丢失RAI 1基因的一个拷贝会导致Smith-Magenis综合征（SMS），这是一种神经发育障碍。使用新生成的SMS小鼠模型，这项研究表明，在出生后早期窗口恢复Rai 1基因剂量可以修复该SMS模型中的基因表达和社会互动缺陷。SMS小鼠模型还显示出前额叶皮层中树突棘的密度降低，树突棘是兴奋性突触的解剖学相关物。人工激活前额叶皮层神经元部分缓解了行为缺陷。这些发现表明，与Rett综合征相似，SMS是由具有可逆发育表型的染色质修饰基因的破坏引起的，突出了儿童或青春期的潜在治疗窗口。视黄酸诱导的1型单倍不足（RAI 1）导致史密斯-马格尼斯综合征（SMS），这是一种与颅面异常、智力残疾和行为问题相关的综合征性自闭症谱系障碍。目前还没有治愈SMS的方法。在这里，我们建立了一个遗传小鼠模型，以确定在Rai 1杂合子小鼠中SMS样神经行为表型的可逆性。我们发现，出生后3-4周的Rai 1水平正常化纠正了与神经发育途径相关的基因表达，并完全逆转了Rai 1单倍性不足引起的社会互动缺陷。相反，Rai 1在出生后7-8周重新激活是没有好处的。我们还证明，正确的Rai 1剂量是需要在兴奋性和抑制性神经元适当的社会互动。最后，我们发现Rai 1杂合子小鼠内侧前额叶皮层（mPFC）的树突棘减少，成年mPFC神经元的光遗传学激活改善了Rai 1杂合子小鼠的社会互动缺陷。总之，这些结果表明存在出生后的时间窗口，在此期间恢复Rai 1可以改善SMS小鼠模型的转录和社会行为缺陷。在这一关键窗口期之后，回路一级的干预措施可能会有所助益。
Losing one copy of the RAI1 gene causes Smith–Magenis syndrome (SMS), a neurodevelopmental disorder. Using a newly generated SMS mouse model, this study demonstrates that restoring the Rai1 gene dose in an early postnatal window could repair gene expression and social interaction deficits in this SMS model. The SMS mouse model also showed a reduced density of dendritic spines, anatomical correlates of excitatory synapses, in the prefrontal cortex. Artificial activation of prefrontal cortex neurons partially alleviated the behavioral deficits. These findings suggest that, similar to Rett syndrome, SMS is caused by disruption of a chromatin-modifying gene with reversible developmental phenotypes, highlighting the potential treatment windows in childhood or adolescence. Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith–Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3–4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7–8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.
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影响因子：
64.8
作者：
Sztainberg Y;Chen HM;Swann JW;Hao S;Tang B;Wu Z;Tang J;Wan YW;Liu Z;Rigo F;Zoghbi HY
通讯作者：
Zoghbi HY
影响因子：
--
作者：
Takahashi, Aki;Miczek, Klaus A
通讯作者：
Miczek, Klaus A
影响因子：
3.8
作者：
Bicks LK;Koike H;Akbarian S;Morishita H
通讯作者：
Morishita H
DOI：
10.1073/pnas.1703477114
发表时间：
2017-05-23
影响因子：
11.1
作者：
Tuttle, Alexander H.;Tansley, Shannon;Mogil, Jeffrey S.
通讯作者：
Mogil, Jeffrey S.
影响因子：
3.5
作者：
Bi, WM;Ohyama, T;Lupski, JR
通讯作者：
Lupski, JR