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Complexin I knockout rats exhibit a complex neurobehavioral phenotype including profound ataxia and marked deficits in lifespan

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Abstract

Complexin I (CPLX1), a presynaptic small molecule protein, forms SNARE complex in the central nervous system involved in the anchoring, pre-excitation, and fusion of axonal end vesicles. Abnormal expression of CPLX1 occurs in several neurodegenerative and psychiatric disorders that exhibit disrupted neurobehaviors. CPLX1 gene knockout induces severe ataxia and social behavioral deficits in mice, which has been poorly demonstrated. Here, to address the limitations of single-species models and to provide translational insights relevant to human diseases, we used CPLX1 knockout rats to further explore the function of the CPLX1 gene. The CRISPR/Cas9 gene editing system was adopted to generate CPLX1 knockout rats (CPLX1−/−). Then, we characterized the survival rate and behavioral phenotype of CPLX1−/− rats using behavioral analysis. To further explain this phenomenon, we performed blood glucose testing, Nissl staining, hematoxylin-eosin staining, and Golgi staining. We found that CPLX1−/− rats showed profound ataxia, dystonia, movement and exploratory deficits, and increased anxiety and sensory deficits but had normal cognitive function. Nevertheless, CPLX1−/− rats could swim without training. The abnormal histomorphology of the stomach and intestine were related to decreased weight and early death in these rats. Decreased dendritic branching was also found in spinal motor neurons in CPLX1−/− rats. In conclusion, CPLX1 gene knockout induced the abnormal histomorphology of the stomach and intestine and decreased dendritic branching in spinal motor neurons, causing different phenotypes between CPLX1−/− rats and mice, even though both of these phenotypes showed profound ataxia. These findings provide a new perspective for understanding the role of CPLX1.

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Funding

This work was supported by the National Natural Science Foundation of China (No. NSF 81471268).

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Authors and Affiliations

  1. Institute of Neurological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University & The Research Units of West China, Chinese Academy of Medical Sciences, Chengdu, 610041, China

    Yang Xu, Xiao-Ming Zhao, Yang-Yang Wang, Liu-Lin Xiong, Xiu-Ying He & Ting-Hua Wang

  2. Department of Basic Medicine, Medical School, Kunming University of Science and Technology, Kunming, 650500, China

    Xiao-Ming Zhao

  3. Institute of Neuroscience, Laboratory Zoology Department, Kunming Medical University, Kunming, 650500, China

    Jia Liu & Ting-Hua Wang

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  1. Yang Xu
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Xu, Y., Zhao, XM., Liu, J. et al. Complexin I knockout rats exhibit a complex neurobehavioral phenotype including profound ataxia and marked deficits in lifespan. Pflugers Arch - Eur J Physiol 472, 117–133 (2020). https://doi.org/10.1007/s00424-019-02337-5

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