Deletions of Cacna2d3 in parvalbumin-expressing neurons leads to autistic-like phenotypes in mice

Autism spectrum disorder (ASD) is a series of highly inherited neurodevelopmental disorders. Loss-of-function (LOF) mutations in the CACNA2D3 gene are associated with ASD. However, the underlying mechanism is unknown. Dysfunction of cortical interneurons (INs) is strongly implicated in ASD. Parvalbu...

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Published in:Neurochemistry international 2023-10, Vol.169, p.105569-105569, Article 105569
Main Authors: Shao, Wei, Zheng, Hang, Zhu, Jingwen, Li, Wenhao, Li, Yifan, Hu, Wenjie, Zhang, Juanjuan, Jing, Liang, Wang, Kai, Jiang, Xiao
Format: Article
Language:English
Subjects:
Autism spectrum disorder
Cacna2d3
Disinhibition
Parvalbumin interneurons
Somatostatin interneurons
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Summary:Autism spectrum disorder (ASD) is a series of highly inherited neurodevelopmental disorders. Loss-of-function (LOF) mutations in the CACNA2D3 gene are associated with ASD. However, the underlying mechanism is unknown. Dysfunction of cortical interneurons (INs) is strongly implicated in ASD. Parvalbumin-expressing (PV) INs and somatostatin-expressing (SOM) INs are the two most subtypes. Here, we characterized a mouse knockout of the Cacna2d3 gene in PV-expressing neurons (PVCre;Cacna2d3f/f mice) or in SOM-expressing neurons (SOMCre;Cacna2d3f/f mice), respectively. PVCre;Cacna2d3f/f mice showed deficits in the core ASD behavioral domains (including impaired sociability and increased repetitive behavior), as well as anxiety-like behavior and improved spatial memory. Furthermore, loss of Cacna2d3 from a subset of PV neurons results in a reduction of GAD67 and PV expression in the medial prefrontal cortex (mPFC). These may underlie the increased neuronal excitability in the mPFC, which contribute to the abnormal social behavior in PVCre;Cacna2d3f/f mice. Whereas, SOMCre;Cacna2d3f/f mice showed no obvious deficits in social, cognitive, or emotional phenotypes. Our findings provide the first evidence suggesting the causal role of Cacna2d3 insufficiency in PV neurons in autism. •Deletions of Cacna2d3 in parvalbumin interneurons caused autistic-related behaviors in mice.•Deletions of Cacna2d3 in somatostatin interneurons showed no autistic-related behaviors in mice.•Decreased inhibitory tone and enhanced excitability in the mPFC may account for the deficits of social behaviors in mice with deletions of Cacna2d3.
ISSN:0197-0186
1872-9754
DOI:10.1016/j.neuint.2023.105569