Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs

IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Molecular Autism Pub Date : 2024-01-31 DOI:10.1186/s13229-024-00587-4
Feipeng Zhu, Qi Shi, Yong-hui Jiang, Yong Q. Zhang, Hui Zhao
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Abstract

SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research.
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自闭症相关 Shank3 突变体犬前额叶皮层锥体神经元的突触功能受损和兴奋性过高
SHANK3 基因是自闭症谱系障碍的一个高度复制的致病基因,在多个 Shank3 突变啮齿动物模型中都得到了很好的表征。与啮齿类动物相比,家犬是研究社会认知的绝佳动物模型,因为它们与人类有着密切的互动关系,并表现出类似的社会行为。利用 CRISPR/Cas9 编辑技术,我们最近生成了一种携带 Shank3 突变的狗模型,它表现出一系列类似自闭症的行为,如社交障碍和焦虑症。然而,这些异常行为背后的神经机制仍有待确定。我们利用 Shank3 突变狗模型来研究 Shank3 突变与神经元功能障碍之间可能存在的关系。我们研究了前额叶皮层(PFC)急性脑切片中锥体神经元的电生理特性和突触传递。我们还使用生物细胞素染色法和高尔基染色法检测了前额叶皮质的树突细化和树突棘形态。我们使用电子显微镜分析了突触后密度。我们建立了一套犬脑切片电生理记录方案,结果发现,与野生型犬相比,Shank3杂合子犬PFC第2/3层锥体神经元的兴奋性突触传递受损,同时树突复杂性和棘突密度降低。突触后密度结构在 Shank3 突变体中也受到损害,但锥体神经元表现出过度兴奋。PFC锥体神经元功能受损与行为改变之间的因果关系尚不清楚。要评估 PFC 在社会行为改变中的作用,还需要进一步的实验,如操纵 PFC 神经元的活动或恢复 Shank3 突变体犬的突触传递。我们的研究证明了将犬脑片作为研究神经元回路和疾病的模型系统的可行性。Shank3单倍体缺陷会导致PFC锥体神经元的形态和功能异常,这支持了Shank3突变狗是研究自闭症的新型有效动物模型的观点。
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来源期刊
Molecular Autism
Molecular Autism GENETICS & HEREDITY-NEUROSCIENCES
CiteScore
12.10
自引率
1.60%
发文量
44
审稿时长
17 weeks
期刊介绍: Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.
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