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Philip E Chen, Michael L Errington, Matthias Kneussel, Guiquan Chen, Alexander J Annala, York H Rudhard, Georg F Rast, Christian G Specht, Cezar M Tigaret, Mohammed A Nassar, Richard G M Morris, Timothy V P Bliss, Ralf Schoepfer
The NMDA receptor (NMDAR) subunit GluN1 is an obligatory component of NMDARs without a known functional homolog and is expressed in almost every neuronal cell type. The NMDAR system is a coincidence detector with critical roles in spatial learning and synaptic plasticity. Its coincidence detection property is crucial for the induction of hippocampal long-term potentiation (LTP). We have generated a mutant mouse model expressing a hypomorph of the Grin1(N598R) allele, which leads to a minority (about 10%) of coincidence detection-impaired NMDARs...
October 2009: Learning & Memory
Agnes Thalhammer, York Rudhard, Cezar M Tigaret, Kirill E Volynski, Dmitri A Rusakov, Ralf Schoepfer
Excitatory synaptic transmission and plasticity are critically modulated by N-methyl-D-aspartate receptors (NMDARs). Activation of NMDARs elevates intracellular Ca(2+) affecting several downstream signaling pathways that involve Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Importantly, NMDAR activation triggers CaMKII translocation to synaptic sites. NMDAR activation failed to induce Ca(2+) responses in hippocampal neurons lacking the mandatory NMDAR subunit NR1, and no EGFP-CaMKIIalpha translocation was observed...
December 13, 2006: EMBO Journal
C M Tigaret, A Thalhammer, G F Rast, C G Specht, Y P Auberson, M G Stewart, R Schoepfer
N-Methyl-D-aspartate (NMDA) receptor (NMDAR) activity regulates the net number of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) at the cell surface by modulating the balance between AMPAR membrane insertion and endocytosis. In this study, we addressed the role of NMDAR subtypes and of NMDAR-mediated Ca2+ influx in the NMDAR-induced endocytosis of GluR2-containing AMPARs in primary murine hippocampal neurons. We found that NMDAR activation enhanced the endocytosis of AMPARs containing the GluR2 splice variants with short, but not long, cytoplasmic tails...
April 2006: Molecular Pharmacology
Verena Pawlak, Bettina J Schupp, Frank N Single, Peter H Seeburg, Georg Köhr
NMDA receptors (NMDARs) play a crucial role for the acquisition of functional AMPARs during Hebbian synaptic plasticity at cortical and hippocampal synapses over a short timescale of seconds to minutes. In contrast, homeostatic synaptic plasticity can occur over longer timescales of hours to days. The induction mechanisms of this activity-dependent synaptic scaling are poorly understood but are assumed to be independent of NMDAR signalling in the cortex. Here we investigated in the hippocampus a potential role of NMDAR-mediated Ca(2+) influx for synaptic scaling of AMPA currents by genetic means...
February 1, 2005: Journal of Physiology
York Rudhard, Matthias Kneussel, Mohammed A Nassar, Georg F Rast, Alexander J Annala, Philip E Chen, Cezar M Tigaret, Isabel Dean, Juergen Roes, Alasdair J Gibb, Stephen P Hunt, Ralf Schoepfer
Precise refinement of synaptic connectivity is the result of activity-dependent mechanisms in which coincidence-dependent calcium signaling by NMDA receptors (NMDARs) under control of the voltage-dependent Mg2+ block might play a special role. In the developing rodent trigeminal system, the pattern of synaptic connections between whisker-specific inputs and their target cells in the brainstem is refined to form functionally and morphologically distinct units (barrelettes). To test the role of NMDA receptor signaling in this process, we introduced the N598R mutation into the native NR1 gene...
March 15, 2003: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
J Jerecic, C H Schulze, P Jonas, R Sprengel, P H Seeburg, J Bischofberger
High Ca(2+) permeability and its control by voltage-dependent Mg(2+) block are defining features of NMDA receptors. These features are lost if the principal NR1 subunit carries an asparagine (N) to arginine (R) substitution in a critical channel site at NR1 position 598. NR1(R) expression from a single allele in gene-targeted NR1(+/R) mice is lethal soon after birth, precluding analysis of altered synaptic functions later in life. We therefore employed the forebrain specific alphaCaMKII promoter to drive tTA-mediated tetracycline sensitive transcription of transgenes for NR1(R) and for lacZ as reporter...
October 19, 2001: Brain Research. Molecular Brain Research
F N Single, A Rozov, N Burnashev, F Zimmermann, D F Hanley, D Forrest, T Curran, V Jensen, O Hvalby, R Sprengel, P H Seeburg
NMDA receptors in mice were mutated by gene targeting to substitute asparagine (N) in position 598 of the NR1 subunit to glutamine (Q) or arginine (R). Animals expressing exclusively the mutated NR1 alleles, NR1(Q/Q) and NR1(-/R) mice, developed a perinatally lethal phenotype mainly characterized by respiratory failure. The dysfunctions were partially rescued in heterozygous mice by the presence of pure wild-type receptors. Thus, NR1(+/Q) mice exhibited reduced life expectancy, with females being impaired in nurturing; NR1(+/R) mice displayed signs of underdevelopment such as growth retardation and impaired righting reflex, and died before weaning...
April 1, 2000: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
N Yamada, M Sudo, H Okado, M Iino, K Tsuzuki, A Miwa, S Ozawa
N-methyl-d-aspartate (NMDA) receptors have attracted a great deal of attention because they are intimately involved in brain development, synaptic plasticity and a variety of neurological disorders. The ability to artificially alter the properties of NMDA receptors in central nervous system (CNS) neurons would be useful for elucidating the physiological roles of these receptors. It would also raise the possibility of gene therapy of neurological diseases caused by malfunction of NMDA receptors. In this study, we constructed three recombinant adenoviruses encoding rat NMDA receptor subunit cDNAs, NMDAR1 (NR1), NMDAR2B (NR2B) and mutant NR1(N598R) in which the asparagine (N) site of the wild-type NR1 was replaced with arginine (R) by site-directed mutagenesis...
May 7, 1999: Brain Research. Molecular Brain Research
P Béhé, P Stern, D J Wyllie, M Nassar, R Schoepfer, D Colquhoun
Co-expression of wild-type and mutated NMDA NR1 (N598R) subunits in Xenopus oocytes has been used to determine the stoichiometry of the NMDA receptor-channel. When expressed together, wild-type NR2A and mutant NR1 (N598R) subunits produced channels with a main conductance of 2.6 pS and a sublevel of 1.2 pS. These conductances were clearly different from those obtained from wild-type NR1 and wild-type NR2A channels which gave characteristic 50 pS events with a 40 pS sublevel. When wild-type and mutant NR1 subunits were co-expressed together with NR2A subunits a different channel type with a main conductance of 15...
November 22, 1995: Proceedings. Biological Sciences
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