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Forebrain Shh overexpression improves cognitive function and locomotor hyperactivity in an aneuploid mouse model of Down syndrome and its euploid littermates
Acta Neuropathologica Communications ( IF 7.1 ) Pub Date : 2021-08-16 , DOI: 10.1186/s40478-021-01237-z
Feng J Gao 1, 2 , Donna Klinedinst 1 , Fabian-Xosé Fernandez 3, 4, 5 , Bei Cheng 6 , Alena Savonenko 7 , Benjamin Devenney 1 , Yicong Li 1 , Dan Wu 8 , Martin G Pomper 6 , Roger H Reeves 1, 2
Affiliation  

Down syndrome (DS) is the leading genetic cause of intellectual disability and causes early-onset dementia and cerebellar hypoplasia. The prevalence of attention deficit hyperactivity disorder is elevated in children with DS. The aneuploid DS mouse model “Ts65Dn” shows prominent brain phenotypes, including learning and memory deficits, cerebellar hypoplasia, and locomotor hyperactivity. Previous studies indicate that impaired Sonic hedgehog (Shh) signaling contributes to neurological phenotypes associated with DS and neurodegenerative diseases. However, because of a lack of working inducible Shh knock-in mice, brain region-specific Shh overexpression and its effects on cognitive function have not been studied in vivo. Here, with Gli1-LacZ reporter mice, we demonstrated that Ts65Dn had reduced levels of Gli1, a sensitive readout of Shh signaling, in both hippocampus and cerebellum at postnatal day 6. Through site-specific transgenesis, we generated an inducible human Shh knock-in mouse, TRE-bi-hShh-Zsgreen1 (TRE-hShh), simultaneously expressing dually-lipidated Shh-Np and Zsgreen1 marker in the presence of transactivator (tTA). Double transgenic mice “Camk2a-tTA;TRE-hShh” and “Pcp2-tTA;TRE-hShh” induced Shh overexpression and activated Shh signaling in a forebrain and cerebellum, respectively, specific manner from the perinatal period. Camk2a-tTA;TRE-hShh normalized locomotor hyperactivity and improved learning and memory in 3-month-old Ts65Dn, mitigated early-onset severe cognitive impairment in 7-month-old Ts65Dn, and enhanced spatial cognition in euploid mice. Camk2a-tTA;TRE-hShh cohort maintained until 600days old showed that chronic overexpression of Shh in forebrain from the perinatal period had no effect on longevity of euploid or Ts65Dn. Pcp2-tTA;TRE-hShh did not affect cognition but mitigated the phenotype of cerebellar hypoplasia in Ts65Dn. Our study provides the first in vivo evidence that Shh overexpression from the perinatal period protects DS brain integrity and enhances learning and memory in normal mice, indicating the broad therapeutic potential of Shh ligand for other neurological conditions. Moreover, the first inducible hShh site-specific knock-in mouse could be widely used for spatiotemporal Shh signaling regulation.

中文翻译:

前脑 Shh 过表达改善唐氏综合症及其整倍体同窝小鼠模型的认知功能和运动过度活跃

唐氏综合症 (DS) 是导致智力障碍的主要遗传原因,并导致早发性痴呆和小脑发育不全。DS患儿的注意力缺陷多动障碍患病率升高。非整倍体 DS 小鼠模型“Ts65Dn”显示出显着的大脑表型,包括学习和记忆缺陷、小脑发育不全和运动过度活跃。先前的研究表明,受损的 Sonic Hedgehog (Shh) 信号传导有助于与 DS 和神经退行性疾病相关的神经表型。然而,由于缺乏可工作的可诱导 Shh 敲入小鼠,尚未在体内研究大脑区域特异性 Shh 过表达及其对认知功能的影响。在这里,使用 Gli1-LacZ 报告小鼠,我们证明 Ts65Dn 降低了 Gli1 水平,这是一种敏感的 Shh 信号读数,在出生后第 6 天在海马和小脑中。通过位点特异性转基因,我们产生了一种可诱导的人类 Shh 敲入小鼠 TRE-bi-hShh-Zsgreen1 (TRE-hShh),同时表达双脂化 Shh-Np 和 Zsgreen1存在反式激活因子 (tTA) 时的标记。双转基因小鼠“Camk2a-tTA;TRE-hShh”和“Pcp2-tTA;TRE-hShh”分别以特定方式在围产期诱导前脑和小脑中的 Shh 过表达和激活 Shh 信号传导。Camk2a-tTA;TRE-hShh 使 3 个月大的 Ts65Dn 的运动过度活跃和改善的学习和记忆,减轻 7 个月大的 Ts65Dn 的早发性严重认知障碍,并增强整倍体小鼠的空间认知。Camk2a-tTA;维持至 600 天龄的 TRE-hShh 队列表明,围产期前脑中 Shh 的慢性过表达对整倍体或 Ts65Dn 的寿命没有影响。Pcp2-tTA;TRE-hShh 不影响认知,但减轻了 Ts65Dn 中小脑发育不全的表型。我们的研究提供了第一个体内证据,表明围产期的 Shh 过表达可以保护 DS 大脑的完整性并增强正常小鼠的学习和记忆,表明 Shh 配体对其他神经系统疾病具有广泛的治疗潜力。此外,第一个诱导型 hShh 位点特异性敲入小鼠可广泛用于时空 Shh 信号调节。我们的研究提供了第一个体内证据,表明围产期的 Shh 过表达可以保护 DS 大脑的完整性并增强正常小鼠的学习和记忆,表明 Shh 配体对其他神经系统疾病具有广泛的治疗潜力。此外,第一个诱导型 hShh 位点特异性敲入小鼠可广泛用于时空 Shh 信号调节。我们的研究提供了第一个体内证据,表明围产期的 Shh 过表达可以保护 DS 大脑的完整性并增强正常小鼠的学习和记忆,表明 Shh 配体对其他神经系统疾病具有广泛的治疗潜力。此外,第一个诱导型 hShh 位点特异性敲入小鼠可广泛用于时空 Shh 信号调节。
更新日期:2021-08-16
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