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- Title
Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel.
- Authors
Seung-Hyun Lee; Yoon-Jung Kim; Youhwa Jo; Soo-Jeong Kim; La-Mee Choi; Se-Young Choi; Tae-Yong Choi; Jae Ryul Bae; Lee, A-Ram; Mi-Ryoung Song; Chul-Seung Park; Kwang Min Lee; Sekyu Choi; Sunhoe Bang; Jongkyeong Chung; Kyung Jin Lee; Sung Hyun Kim
- 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.
- Subjects
COGNITIVE ability; GENETIC mutation; INTELLECTUAL disabilities; GLUTAMIC acid; NEUROPLASTICITY
- Publication
Journal of Neuroscience, 2018, Vol 38, Issue 14, p3571
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2081-17.2018