Inositol 1,4,5-trisphosphate 3-kinase A overexpressed in mouse forebrain modulates synaptic transmission and mGluR-LTD of CA1 pyramidal neurons.
Inositol 1,4,5-trisphosphate 3-kinase A overexpressed in mouse forebrain modulates synaptic transmission and mGluR-LTD of CA1 pyramidal neurons.
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DOI：
10.1371/journal.pone.0193859
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Kim H
中科院分区：
文献类型：
--
作者：
Choi B;Lee HW;Mo S;Kim JY;Kim HW;Rhyu IJ;Hong E;Lee YK;Choi JS;Kim CH;Kim H
肌醇 1,4,5-三磷酸 3-激酶 A (IP3K-A) 调节肌醇多磷酸、肌醇三磷酸 (IP3) 和肌醇四磷酸的水平，以调节中枢神经系统中的细胞信号传导和细胞内钙稳态。 IP3K-A 以活性依赖性方式与 F-肌动蛋白结合，并在树突棘中积累，参与突触可塑性的调节。 IP3K-A 敲除小鼠在某些形式的海马依赖性学习和突触可塑性方面表现出缺陷，例如海马齿状回突触的长期增强。在本研究中，为了进一步阐明 IP3K-A 在大脑中的作用，我们开发了一种转基因 (Tg) 小鼠系，其中 IP3K-A 在前脑区域（包括海马）的兴奋性神经元中条件性过表达约 3 倍。 Tg 小鼠表现出诱发反应的突触前释放概率增加，突触小泡池更大，兴奋性突触后电流幅度更小，但棘密度或突触后密度相关蛋白 NR2B、突触结合蛋白 1 和 PSD-95 的表达水平未受影响。 Tg 小鼠的海马依赖性学习和记忆任务，包括新物体识别和径向臂迷宫任务，部分受损。此外，(R,S)-3,5-二羟基苯基甘氨酸诱导的代谢型谷氨酸受体长期抑制在 Tg 小鼠中受到抑制，并且这种抑制依赖于蛋白激酶 C，而不依赖于 IP3 受体。 Tg 小鼠中依赖于 N-甲基-d-天冬氨酸受体的长时程增强和抑制受到轻微影响。总之，本研究表明，过表达的 IP3K-A 通过调节突触前和突触后功能，在某些形式的海马依赖性学习和记忆任务以及突触传递和可塑性中发挥作用。
Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) regulates the level of the inositol polyphosphates, inositol trisphosphate (IP3) and inositol tetrakisphosphate to modulate cellular signaling and intracellular calcium homeostasis in the central nervous system. IP3K-A binds to F-actin in an activity-dependent manner and accumulates in dendritic spines, where it is involved in the regulation of synaptic plasticity. IP3K-A knockout mice exhibit deficits in some forms of hippocampus-dependent learning and synaptic plasticity, such as long-term potentiation in the dentate gyrus synapses of the hippocampus. In the present study, to further elucidate the role of IP3K-A in the brain, we developed a transgenic (Tg) mouse line in which IP3K-A is conditionally overexpressed approximately 3-fold in the excitatory neurons of forebrain regions, including the hippocampus. The Tg mice showed an increase in both presynaptic release probability of evoked responses, along with bigger synaptic vesicle pools, and miniature excitatory postsynaptic current amplitude, although the spine density or the expression levels of the postsynaptic density-related proteins NR2B, synaptotagmin 1, and PSD-95 were not affected. Hippocampal-dependent learning and memory tasks, including novel object recognition and radial arm maze tasks, were partially impaired in Tg mice. Furthermore, (R,S)-3,5-dihydroxyphenylglycine-induced metabotropic glutamate receptor long-term depression was inhibited in Tg mice and this inhibition was dependent on protein kinase C but not on the IP3 receptor. Long-term potentiation and depression dependent on N-methyl-d-aspartate receptor were marginally affected in Tg mice. In summary, this study shows that overexpressed IP3K-A plays a role in some forms of hippocampus-dependent learning and memory tasks as well as in synaptic transmission and plasticity by regulating both presynaptic and postsynaptic functions.
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