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Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel

Authors
Choi, Tae-YongLee, Seung-HyunKim, Yoon-JungBae, Jae RyulLee, Kwang MinJo, YouhwaKim, Soo-JeongLee, A-RamChoi, SekyuChoi, La-MeeBang, SunhoeSong, Mi-RyoungChung, JongkyeongLee, Kyung JinKim, Sung HyunPark, Chul-SeungChoi, Se-Young
Issue Date
Apr-2018
Publisher
SOC NEUROSCIENCE
Keywords
BK channels; CRBN; intellectual disability; neurotransmitter release; presynaptic
Citation
JOURNAL OF NEUROSCIENCE, v.38, no.14, pp.3571 - 3583
Journal Title
JOURNAL OF NEUROSCIENCE
Volume
38
Number
14
Start Page
3571
End Page
3583
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/746
DOI
10.1523/JNEUROSCI.2081-17.2018
ISSN
0270-6474
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 CrbnKOmice. These results strongly suggest that increased BK channel activity is the pathological mechanism of intellectual disability in CRBN mutations.
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Choi, Tae-Yong
연구본부 (정서·인지질환 연구그룹)
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