2. Academic Validation
  3. Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel

Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel

  • J Neurosci. 2018 Apr 4;38(14):3571-3583. doi: 10.1523/JNEUROSCI.2081-17.2018.
Tae-Yong Choi 1 2,  Seung-Hyun Lee 1,  Yoon-Jung Kim 1,  Jae Ryul Bae 3,  Kwang Min Lee 4 5,  Youhwa Jo 1,  Soo-Jeong Kim 1,  A-Ram Lee 4,  Sekyu Choi 6,  La-Mee Choi 1,  Sunhoe Bang 6,  Mi-Ryoung Song 4,  Jongkyeong Chung 6,  Kyung Jin Lee 7,  Sung Hyun Kim 8,  Chul-Seung Park 9,  Se-Young Choi 10
Affiliations

Affiliations

  • 1 Department of Physiology and Dental Research Institute, Seoul National University School of Dentistry, Seoul 03080, Republic of Korea.
  • 2 Department of Neural Development and Disease, Korea Brain Research Institute, Daegu 41068, Republic of Korea.
  • 3 Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 4 School of Life Sciences, Gwangju Institute Science and Technology, Gwangju 61005, Republic of Korea.
  • 5 Korea Food Research Institute, Seongnam, Gyeonggi 13539, Republic of Korea.
  • 6 National Creative Research Initiatives Center for Energy Homeostasis Regulation, Institute of Molecular Biology and Genetics and School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • 7 Department of Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea, and.
  • 8 Department of Physiology, School of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea.
  • 9 School of Life Sciences, Gwangju Institute Science and Technology, Gwangju 61005, Republic of Korea, cspark@gist.ac.kr sychoi@snu.ac.kr.
  • 10 Department of Physiology and Dental Research Institute, Seoul National University School of Dentistry, Seoul 03080, Republic of Korea, cspark@gist.ac.kr sychoi@snu.ac.kr.
PMID: 29530986 DOI: 10.1523/JNEUROSCI.2081-17.2018
Abstract

Mutations in the Cereblon (CRBN) gene cause human intellectual disability, one of the most common cognitive disorders. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. We investigated the role of CRBN in synaptic function and animal behavior using male mouse and Drosophila models. Crbn knock-out (KO) mice showed normal brain and spine morphology as well as intact synaptic plasticity; however, they also exhibited decreases in synaptic transmission and presynaptic release probability exclusively in excitatory synapses. Presynaptic function was impaired not only by loss of CRBN expression, but also by expression of pathogenic CRBN mutants (human R419X mutant and Drosophila G552X mutant). We found that the BK channel blockers paxilline and iberiotoxin reversed this decrease in presynaptic release probability in Crbn KO mice. In addition, paxilline treatment also restored normal cognitive behavior in Crbn KO mice. These results strongly suggest that increased BK channel activity is the pathological mechanism of intellectual disability in CRBN mutations.SIGNIFICANCE STATEMENTCereblon (CRBN), a well known target of the immunomodulatory drug thalidomide, was originally identified as a gene that causes human intellectual disability when mutated. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. Based on the idea that synaptic abnormalities are the most common factor in cognitive dysfunction, we monitored the synaptic structure and function of Crbn knock-out (KO) Animals to identify the molecular mechanisms of intellectual disability. Here, we found that Crbn KO Animals showed cognitive deficits caused by enhanced BK channel activity and reduced presynaptic glutamate release. Our findings suggest a physiological pathomechanism of the intellectual disability-related gene CRBN and will contribute to the development of therapeutic strategies for CRBN-related intellectual disability.

Keywords

BK channels; CRBN; intellectual disability; neurotransmitter release; presynaptic.

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