title: The glutamate receptor GluN2 subunit regulates synaptic trafficking of AMPA receptors in the neonatal mouse brain.
abstract: 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.
authors.affiliation: Division of Neuronal Network, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Hamada
authors.forename: Itone
authors.initials: I
authors.lastname: Ogawa
authors.forename: Miwako
authors.initials: M
authors.lastname: Yamasaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kiyama
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kassai
authors.forename: Ayako M
authors.initials: AM
authors.lastname: Watabe
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakao
authors.forename: Atsu
authors.initials: A
authors.lastname: Aiba
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Toshiya
authors.initials: T
authors.lastname: Manabe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D051379:Mice; D021381:Protein Transport; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
chemical_list: D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor
keywords: NMDA receptor; TARP; hippocampus; miniature EPSC; postsynaptic density