期刊
MOLECULAR PSYCHIATRY
卷 24, 期 7, 页码 1079-1092出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41380-018-0338-4
关键词
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资金
- Foundation of Growth Science
- Japan Epilepsy Research Foundation
- Takeda Science Foundation
- Uehara Memorial Foundation
- Ichiro Kanehara Foundation
- CREST, JST [JPMJCR1XM5]
- JST PRESTO Program: Development and Foundation of Neural Networks
- [25871060]
- [17K01975]
- [25290021]
- [25282242]
- [26640039]
- [16K14592]
- [24650183]
- [15K15730]
Calcium/calmodulin-dependent serine protein kinase (CASK) is a membrane-associated guanylate kinase (MAGUK) protein that is associated with neurodevelopmental disorders. CASK is thought to have both pre- and postsynaptic functions, but the mechanism and consequences of its functions in the brain have yet to be elucidated, because homozygous CASK-knockout (CASK-KO) mice die before brain maturation. Taking advantage of the X-chromosome inactivation (XCI) mechanism, here we examined the synaptic functions of CASK-KO neurons in acute brain slices of heterozygous CASK-KO female mice. We also analyzed CASK-knockdown (KD) neurons in acute brain slices generated by in utero electroporation. Both CASK-KO and CASK-KD neurons showed a disruption of the excitatory and inhibitory (E/I) balance. We further found that the expression level of the N-methyl-D-aspartate receptor subunit GluN2B was decreased in CASK-KD neurons and that overexpressing GluN2B rescued the disrupted E/I balance in CASK-KD neurons. These results suggest that the downregulation of GluN2B may be involved in the mechanism of the disruption of synaptic E/I balance in CASK-deficient neurons.
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