The glutamate receptor GluN2 subunit regulates synaptic trafficking of AMPA receptors in the neonatal mouse brain
The glutamate receptor GluN2 subunit regulates synaptic trafficking of AMPA receptors in the neonatal mouse brain
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DOI：
10.1111/ejn.12682
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发表时间：
2014-10
影响因子：
3.4
通讯作者：
S. Hamada;Itone Ogawa;Miwako Yamasaki;Y. Kiyama;Hidetoshi Kassai;A. M. Watabe;K. Nakao;A. Aiba;Masahiko Watanabe;T. Manabe
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文献类型：
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作者：
S. Hamada;Itone Ogawa;Miwako Yamasaki;Y. Kiyama;Hidetoshi Kassai;A. M. Watabe;K. Nakao;A. Aiba;Masahiko Watanabe;T. Manabe
N-甲基-d-天冬氨酸受体（NMDAR）在神经发育、突触可塑性和神经元细胞死亡中起着多种生理和病理作用。它由两个GluN 1和两个GluN 2亚基组成，在新生儿海马中，大多数突触NMDAR是含GluN 2B的受体，在发育过程中逐渐被含GluN 2A的受体取代。在这里，我们通过分析GluN 2A取代GluN 2B的敲入（KI）小鼠来研究GluN 2A是否可以在神经发育和功能中取代GluN 2B。KI突变是致命的，尽管含GluN 2A的受体即使在没有GluN 2B的情况下也被转运到突触后膜，并且在出生后第0天的急性海马切片的突触处起作用，这表明含GluN 2A的NMDAR不能取代含GluN 2B的NMDAR。重要的是，在KI小鼠中，突触α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）亚基GluA 1增加，并且参与AMPAR突触运输的跨膜AMPAR调节蛋白增加。虽然在培养的神经元中已经报道了GluN 2B对AMPAR的调节，但我们在这里发现，AMPAR介导的突触反应在急性KI切片中增加，表明GluN 2A和GluN 2B在体内AMPAR表达和运输中的不同作用。综上所述，我们的研究结果表明，GluN 2B是必不可少的动物的生存，和GluN 2B-GluN 2A开关在AMPAR的突触整合中起着至关重要的作用，通过调节GluA 1在整个动物。
The N‐methyl‐d‐aspartate receptor (NMDAR) plays various physiological and pathological roles in neural development, synaptic plasticity and neuronal cell death. It is composed of two GluN1 and two GluN2 subunits and, in the neonatal hippocampus, most synaptic NMDARs are GluN2B‐containing receptors, which are gradually replaced with GluN2A‐containing receptors during development. Here, we examined whether GluN2A could be substituted for GluN2B in neural development and functions by analysing knock‐in (KI) mice in which GluN2B is replaced with GluN2A. The KI mutation was neonatally lethal, although GluN2A‐containing receptors were transported to the postsynaptic membrane even without GluN2B and functional at synapses of acute hippocampal slices of postnatal day 0, indicating that GluN2A‐containing NMDARs could not be substituted for GluN2B‐containing NMDARs. Importantly, the synaptic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor (AMPAR) subunit GluA1 was increased, and the transmembrane AMPAR regulatory protein, which is involved in AMPAR synaptic trafficking, was increased in KI mice. Although the regulation of AMPARs by GluN2B has been reported in cultured neurons, we showed here that AMPAR‐mediated synaptic responses were increased in acute KI slices, suggesting differential roles of GluN2A and GluN2B in AMPAR expression and trafficking in vivo. Taken together, our results suggest that GluN2B is essential for the survival of animals, and that the GluN2B–GluN2A switching plays a critical role in synaptic integration of AMPARs through regulation of GluA1 in the whole animal.