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Major motor and gait deficits with sexual dimorphism in a Shank3 mutant mouse model
Molecular Autism ( IF 6.3 ) Pub Date : 2021-01-19 , DOI: 10.1186/s13229-020-00412-8
Emmanuel Matas 1 , Alexandre Maisterrena 1 , Mathieu Thabault 1 , Eric Balado 1 , Maureen Francheteau 1 , Anais Balbous 1, 2 , Laurie Galvan 1 , Mohamed Jaber 1, 2
Affiliation  

Contrasting findings were reported in several animal models with a Shank3 mutation used to induce various autism spectrum disorder (ASD) symptoms. Here, we aimed at investigating behavioral, cellular, and molecular consequences of a C-terminal (frameshift in exon 21) deletion in Shank3 protein in mice, a mutation that is also found in clinical conditions and which results in loss of major isoforms of Shank3. A special focus was made on cerebellar related parameters. All three genotypes were analyzed [wild type (WT), heterozygote (Shank3+/ΔC) and homozygote (Shank3 ΔC/ΔC)] and males and females were separated into two distinct groups. Motor and social behavior, gait, Purkinje cells (PC) and glutamatergic protein levels were determined. Behavioral and cellular procedures used here were previously validated using two environmental animal models of ASD. ANOVA and post-hoc analysis were used for statistical analysis. Shank3 ΔC/ΔC mice showed significant impairments in social novelty preference, stereotyped behavior and gait. These were accompanied by a decreased number of PC in restricted cerebellar sub-regions and decreased cerebellar expression of mGluR5. Females Shank3 ΔC/ΔC were less affected by the mutation than males. Shank3+/ΔC mice showed impairments only in social novelty preference, grooming, and decreased mGluR5 expression and that were to a much lesser extent than in Shank3 ΔC/ΔC mice. As Shank3 mutation is a haploinsufficiency, it is of interest to emphasize that Shank3+/ΔC mice showed only mild to no deficiencies compared to Shank3 ΔC/ΔC. Our findings indicate that several behavioral, cellular, and molecular parameters are affected in this animal model. The reported deficits are more pronounced in males than in females. Additionally, male Shank3 ΔC/ΔC mice show more pronounced alterations than Shank3+/ΔC. Together with our previous findings in two environmental animal models of ASD, our studies indicate that gait dysfunction constitutes a robust set of motor ASD symptoms that may be considered for implementation in clinical settings as an early and quantitative diagnosis criteria.

中文翻译:

Shank3 突变小鼠模型中的主要运动和步态缺陷与性别二态性

在具有用于诱发各种自闭症谱系障碍 (ASD) 症状的 Shank3 突变的几种动物模型中报告了对比结果。在这里,我们旨在研究小鼠 Shank3 蛋白 C 末端(外显子 21 移码)缺失的行为、细胞和分子后果,该突变也在临床条件下发现,导致 Shank3 的主要同种型丢失. 特别关注小脑相关参数。分析了所有三种基因型 [野生型 (WT)、杂合子 (Shank3+/ΔC) 和纯合子 (Shank3 ΔC/ΔC)],并将雄性和雌性分为两个不同的组。测定了运动和社会行为、步态、浦肯野细胞 (PC) 和谷氨酸能蛋白水平。此处使用的行为和细胞程序先前已使用两种 ASD 环境动物模型进行了验证。方差分析和事后分析用于统计分析。Shank3 ΔC/ΔC 小鼠在社交新奇偏好、刻板行为和步态方面表现出显着损害。这些伴随着受限小脑亚区域中 PC 数量的减少和 mGluR5 小脑表达的减少。与男性相比,女性 Shank3 ΔC/ΔC 受突变的影响较小。Shank3+/ΔC 小鼠仅在社交新奇偏好、修饰和降低的 mGluR5 表达方面表现出损伤,并且比 Shank3 ΔC/ΔC 小鼠的程度要小得多。由于 Shank3 突变是一种单倍体不足,需要强调的是,与 Shank3 ΔC/ΔC 相比,Shank3+/ΔC 小鼠仅表现出轻微或没有缺陷。我们的研究结果表明,该动物模型中的一些行为、细胞和分子参数受到影响。报告的缺陷在男性中比在女性中更为明显。此外,雄性 Shank3 ΔC/ΔC 小鼠表现出比 Shank3+/ΔC 更明显的改变。连同我们之前在两个 ASD 环境动物模型中的发现,我们的研究表明,步态功能障碍构成了一组强大的运动 ASD 症状,可以考虑在临床环境中作为早期和定量诊断标准实施。
更新日期:2021-01-19
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