Affordable Access

Access to the full text

Social Deficits and Cerebellar Degeneration in Purkinje Cell Scn8a Knockout Mice

Authors
  • Yang, Xiaofan1, 2
  • Yin, Hongqiang3, 4
  • Wang, Xiaojing2
  • Sun, Yueqing2
  • Bian, Xianli5
  • Zhang, Gaorui6
  • Li, Anning6
  • Cao, Aihua1
  • Li, Baomin1
  • Ebrahimi-Fakhari, Darius7
  • Yang, Zhuo3
  • Meisler, Miriam H.8, 9
  • Liu, Qiji2, 10
  • 1 Department of Pediatrics, Qilu Hospital of Shandong University, Jinan , (China)
  • 2 Key Laboratory of Experimental Teratology, Ministry of Education, Department of Genetics, School of Basic Medical Sciences, Shandong University, Jinan , (China)
  • 3 Medical School, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for Ministry of Education, Nankai University, Tianjin , (China)
  • 4 Department of Operational Medicine, Tianjin Institute of Environmental & Operational Medicine, Tianjin , (China)
  • 5 Department of Neurology, Second Hospital of Shandong University, Jinan , (China)
  • 6 Department of Radiology, Qilu Hospital of Shandong University, Jinan , (China)
  • 7 Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA , (United States)
  • 8 Department of Human Genetics, University of Michigan, Ann Arbor, MI , (United States)
  • 9 Department of Neurology, University of Michigan, Ann Arbor, MI , (United States)
  • 10 Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province, Jinan , (China)
Type
Published Article
Journal
Frontiers in Molecular Neuroscience
Publisher
Frontiers Media SA
Publication Date
Apr 26, 2022
Volume
15
Identifiers
DOI: 10.3389/fnmol.2022.822129
Source
Frontiers
Keywords
Disciplines
  • Molecular Neuroscience
  • Original Research
License
Green

Abstract

Mutations in the SCN8A gene encoding the voltage-gated sodium channel α-subunit Nav1. 6 have been reported in individuals with epilepsy, intellectual disability and features of autism spectrum disorder. SCN8A is widely expressed in the central nervous system, including the cerebellum. Cerebellar dysfunction has been implicated in autism spectrum disorder. We investigated conditional Scn8a knockout mice under C57BL/6J strain background that specifically lack Scn8a expression in cerebellar Purkinje cells (Scn8aflox/flox, L7Cre+ mice). Cerebellar morphology was analyzed by immunohistochemistry and MR imaging. Mice were subjected to a battery of behavioral tests including the accelerating rotarod, open field, elevated plus maze, light-dark transition box, three chambers, male-female interaction, social olfaction, and water T-maze tests. Patch clamp recordings were used to evaluate evoked action potentials in Purkinje cells. Behavioral phenotyping demonstrated that Scn8aflox/flox, L7Cre+ mice have impaired social interaction, motor learning and reversal learning as well as increased repetitive behavior and anxiety-like behaviors. By 5 months of age, Scn8aflox/flox, L7Cre+ mice began to exhibit cerebellar Purkinje cell loss and reduced molecular thickness. At 9 months of age, Scn8aflox/flox, L7Cre+ mice exhibited decreased cerebellar size and a reduced number of cerebellar Purkinje cells more profoundly, with evidence of additional neurodegeneration in the molecular layer and deep cerebellar nuclei. Purkinje cells in Scn8aflox/flox, L7Cre+ mice exhibited reduced repetitive firing. Taken together, our experiments indicated that loss of Scn8a expression in cerebellar Purkinje cells leads to cerebellar degeneration and several ASD-related behaviors. Our study demonstrated the specific contribution of loss of Scn8a in cerebellar Purkinje cells to behavioral deficits characteristic of ASD. However, it should be noted that our observed effects reported here are specific to the C57BL/6 genome type.

Report this publication

Statistics

Seen <100 times