Neuron, Vol. 16, 333–344, February, 1996, Copyright 1996 by Cell Press Impairment of Suckling Response, Trigeminal Neuronal Pattern Formation, and Hippocampal LTD in NMDA Receptor 2 Subunit Mutant Mice Tatsuya Kutsuwada, 1,2 * Kenji Sakimura, 1 * The mutation hindered the formation of the whisker- related neuronal barrelette structure and the cluster- Toshiya Manabe, 3 Chitoshi Takayama, 4 ing of primary sensory afferent terminals in the brain- Nobuo Katakura, 5 Etsuko Kushiya, 1 Rie Natsume, 1 stem trigeminal nucleus. In the hippocampus of the Masahiko Watanabe, 4 Yoshiro Inoue, 4 Takeshi Yagi, 6 † mutant mice, synaptic NMDA responses and long- Shinichi Aizawa, 6 ‡ Masaaki Arakawa, 2 term depression were abolished. These results sug- Tomoyuki Takahashi, 3 Yoshio Nakamura, 5 gest that the 2 subunit plays an essential role in both Hisashi Mori, 7 and Masayoshi Mishina 1,7 neuronal pattern formation and synaptic plasticity. 1 Department of Neuropharmacology Brain Research Institute Introduction 2 Department of Internal Medicine II Faculty of Medicine The N-methyl- D-aspartate (NMDA) receptor channel is Niigata University unique in functional properties among many neurotrans- Niigata 951 mitter receptors and ion channels mediating neural sig- Japan naling in the brain. The NMDA receptor channel is gated 3 Department of Neurophysiology by both ligands and voltage, and is highly permeable to Institute for Brain Research Ca 2+ (Mayer et al., 1984; Nowak et al., 1984; Ascher and Faculty of Medicine Nowak, 1986; MacDermott et al., 1986). These charac- University of Tokyo teristics of the NMDA receptor channel directly relate Tokyo 113 to its important physiological roles in synaptic plasticity Japan as a molecular coincidence detector. Some forms of 4 Department of Anatomy long-term potentiation (LTP) and long-term depression Hokkaido University School of Medicine (LTD), which are thought to underlie learning and mem- Sapporo 060 ory, are critically dependent on the NMDA receptor Japan channel (Bliss and Collingridge, 1993; Malenka and Ni- 5 Department of Physiology coll, 1993). The NMDA receptor channel is also involved Faculty of Dentistry in neuronal pattern formation during development (Cline Tokyo Medical and Dental University et al., 1987; Kleinschmidt et al., 1987). Tokyo 113 One of the most important findings obtained by recent Japan molecular cloning is the elucidation of the molecular 6 Laboratory of Molecular Oncology diversity of the NMDA receptor channel (Ikeda et al., Tsukuba Life Science Center 1992; Kutsuwada et al., 1992; Meguro et al., 1992; Mo- Institute of Physical and Chemical Research nyer et al., 1992). Highly active NMDA receptor channel Ibaraki 305 is formed in vitro by coexpression of two members of Japan glutamate receptor (GluR) channel subunit families, i.e., 7 Department of Pharmacology the GluR (the fifth subfamily or NR2) and GluR (the Faculty of Medicine sixth subfamily or NR1) subunit families (Ikeda et al., University of Tokyo 1992; Kutsuwada et al., 1992; Meguro et al., 1992; Mo- Tokyo 113 nyer et al., 1992), although the 1 (NMDAR1) subunit Japan alone exhibits a very small response at least in the Xeno- pus oocyte expression system (Moriyoshi et al., 1991; Yamazaki et al., 1992). In accord with this, most brain Summary regions express both the  and  subunit mRNAs, and no NMDA responses have been reported for maturated Multiple  subunits are major determinants of the cerebellar Purkinje cells that express the 1 subunit but NMDA receptor channel diversity. Based on their func- none of the  subunits (Quinlan and Davies, 1985; Perkel tional properties in vitro and distributions, we have et al., 1990; Watanabe et al., 1992, 1994a; Brose et al., proposed that the 1 and 2 subunits play a role in 1993; Monyer et al., 1994). There are four members in synaptic plasticity. To investigate the physiological the  subunit family (Ikeda et al., 1992; Kutsuwada et significance of the NMDA receptor channel diversity, al., 1992; Meguro et al., 1992; Monyer et al., 1992), we generated mutant mice defective in the 2 subunit. whereas only one member is known in the  subunit These mice showed no suckling response and died family, except for the splice variants (Moriyoshi et al., shortly after birth but could survive by hand feeding. 1991; Yamazaki et al., 1992). At the embryonic stages, the 2 (NR2B) subunit mRNA is expressed in the entire *These authors contributed equally to this work. brain, and the 4 (NR2D) subunit mRNA in the dienceph- † Present address: Laboratory of Neurobiology and Behavioral Ge- alon and the brainstem (Watanabe et al., 1992). After netics, National Institute for Physiological Sciences, Okazaki 444, birth, the 1 (NR2A) subunit mRNA appears in the entire Japan. brain, and the 3 (NR2C) subunit mRNA mainly in the ‡ Present address: Laboratory of Morphogenesis, Instituteof Molec- cerebellum. Expression of the 2 subunit mRNA be- ular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto 860, Japan. comes restricted to the forebrain, and that of the 4 CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector