Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B
Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B
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DOI：
10.1038/s41380-018-0338-4
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发表时间：
2019-07-01
影响因子：
11
通讯作者：
Tabuchi, Katsuhiko
中科院分区：
文献类型：
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作者：
Mori, Takuma;Kasem, Enas A.;Tabuchi, Katsuhiko
钙/钙调素依赖性丝氨酸蛋白激酶（CASK）是一种与神经发育障碍相关的膜相关鸟苷酸激酶（MAGUK）蛋白。CASK被认为具有突触前和突触后功能，但其在大脑中功能的机制和后果尚未阐明，因为纯合子CASK敲除（CASK- ko）小鼠在大脑成熟之前死亡。利用x染色体失活（XCI）机制，我们在杂合CASK-KO雌性小鼠急性脑切片中检测了CASK-KO神经元的突触功能。我们还分析了子宫内电穿孔产生的急性脑切片中的cask -敲低（KD）神经元。CASK-KO和CASK-KD神经元均表现出兴奋性和抑制性（E/I）平衡的破坏。我们进一步发现，n -甲基- d -天冬氨酸受体亚基GluN2B在CASK-KD神经元中的表达水平降低，过表达GluN2B可以恢复CASK-KD神经元中被破坏的E/I平衡。这些结果提示GluN2B的下调可能参与了cask缺陷神经元突触E/I平衡被破坏的机制。
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.