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NMDA Receptor Transgenic Mice These pages detail the mice that have altered levels of NMDA receptor subunit expression. Most of these mice are global knockouts, ie. the expression of a functional product of the gene of interest has been abolished throughout the brain. The NR1 conditional knockout represents a mouse model in which the deletion of NR1 expression is located to specific regions of the brain, a technique that is becoming widely used. Two of the mouse strains represent knock-ins i.e. a subunit has been over-expressed. Click on the names to reach information regarding transgenic models for the different NMDA receptor subunits. |
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NMDAR1 Subunit Knockout Mice The expression of the NMDA receptor subunit NR1 has been modified by a number of groups using either homologous recombination in embryonic stem (ES) cells or regional specific knockout using the cre-loxP method. Studies such as these have demonstrated that expression of the NR1 subunit is essential to NMDA receptor function, somatosensory map formation and neonatal survival. The deleterious developmental effects of NR1 knockout are not due an inability of immature neocortical neurons to migrate or differentiate. Recent work has also suggested that the NR1 subunit (and by inference the NMDA receptor itself) plays a neuroprotective role during the critical period immediately after birth when neuronal pruning and selected cell death occurs. Global loss of the NR1 subunit results in a reduction in the size of the ventrobasal nucleus of the thalamus and an large increase in apoptosis. A conditional knockout mouse in which the NR1 subunit is deleted from excitatory cortical cells has been used to demonstrate that cortical NMDA receptor activity is required to form maps in the somatosensory cortex, but that maps in the brain stem are normal (cf global NR1 knockouts). Thus it would appear that local NMDA receptor activation is required for somatosensory map formation. In addition NMDA receptor-mediated synaptic plasticity in CA1 hippocampal neurones appears to be important in the aquisition and representation of spatial information, whereas plasticity in CA3 neurones may be involved in associative memory. Re-activation of NMDA receptors have also been shown to be necessary for the consolidation of recently acquired memories. Recent evidence also indicates that certain forms of non-spatial memory may also be dependent on the presence of NMDA receptors in hippocampal CA1 neurons. Two point mutations of the NR1 subunit have also been expressed in mice, producing complex phenotypic and functional changes. Mutation of asparagine (N) 598 to either a glutamine (Q) or arginine (R) results in severe dysfunction of autonomic brain function immediately following birth.The mutations decrease the calcium permeability of the NMDA receptor complex and, in the case of the N598Q mutation, the characteristic voltage-dependent magnesium is dominated by a similar calcium block at depolarising potentials but increased calcium flux at resting membrane potentials. Homozygous mice carrying either mutation are unable to breathe or feed and die within 1 hour of birth. This phenotype can be partially rescued by heterozygous expression of the mutation - in this case mice can survive for weeks (N598R) or months (N598Q). In addition, the severity of the phenotype exhibited by the heterozygotic mice azppears to be dependent on the dominance of the mutant subunit in a mixed receptor complex. Such mixed receptors, in which both native and mutant subunits are present, should constitute half the receptor population. In the case of the N598Q mutation, the native subunit is functially dominant and so the increased mortality of these mice is due to the pure mutant receptors (25 % of the total population. However, the N598R mutant subunit is dominant over the native, resulting in a much greater proportion of the NMDA receptor population wityh reduced calcium permeability and no voltage-dependent magnesium block resulting in a more severe phenotype. It should also be noted, however, that the presence of 25% native receptors is sufficient for the formation of normal somatosensory maps (cf global NR1 knockouts) |
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1)
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NR1 global knockout |
Last updated: 9th December 2004
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generated by homolgous recombination in ES cells | |
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NR1 expression lost thoughout the brain | |
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NR2B expression reduced | |
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complete loss of the NMDA-induced rise in intracellular calcium | |
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complete loss of formation of whisker-related patterns ('barrels') in the brainstem | |
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lethal within a day of birth (10 hours, cf NR2B global knockout) | |
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rescued by ectopic expression of the NR1-1a splice variant | |
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viability is dependent on level of NR1-1a expression | |
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extent of somatosensory map formation dependent on expression level of NR1-1a | |
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migration of neocortical neurons is normal - possible compensatory mechanisms | |
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3-5 fold increase in cell death in the ventrobasal nucleus of the thalamus (VB), beginning at day of birth | |
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significant reduction in the size of the VB starting before birth (E17.5) | |
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Forrest D., Yuzaki M., Soares H.D., Ng L., Luk D.C., Sheng M., Stewart C.L., Morgan J.I., Connor J.A. and Curran T. (1994) Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Neuron 13; 325-338 [Medline] [TBase] Li Y., Erzurumlu R.S., Chen C., Jhaveri S. and Tonegawa S. (1994) Whisker-related neuronal patterns fail to develop in the trigeminal brainstem nuclei of NMDAR1 knockout mice. Cell 76; 427-437 [Medline] Iwasato T., Erzurumlu R.S., Huerta P.T., Chen D.F. Sasoka T., Ulupinar E. and Tonegawa S. (1997) NMDA receptor-dependent refinement of somatotopic maps. Neuron 19; 1201-1210 [Medline] Messersmith E.K., Feller M.B., Zhang H. and Shatz C.J. (1997) Migration of neocortical neurons in the absence of functional NMDA receptors. Mol. Cell. Neurosci. 9; 347-57 [Medline] Adams S.M., de Rivero Vaccari J.C. and Corriveau R.A. (2004) Pronounced
cell death in the absence of NMDA receptors in the developing somatosensory
thalamus. J. Neurosci. 24; 9441-9450 [Medline]
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2) |
NR1 global knockout |
Last updated:
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generated by homolgous recombination in ES cells |
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express only 5-10% of normal levels of NR1 | |
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develop to normal size and weight | |
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show increased motor activity during habituation to new environment | |
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increased stereotypic movements | |
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social behaviour deficits - lower levels of social investigation and increased escape behaviour | |
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abnormal sexual function | |
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behavioural and locomotor deficits are reduced following treatment with clozapine | |
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behavioural deficits are related to schizophrenia | |
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Mohn A.R., Gainetdinov R.R., Caron M.C. and Koller B.H. (1999) Mice with reduced NMDA receptor expression display behaviours related to schizophrenia. Cell 98; 427-436 [Medline][TBase] |
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3) |
NR1 conditional knockout - hippocampal CA1 deletion |
Last updated: 9th December
2004
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generated by cre-loxP recombination | |
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loss of NR1 expression restricted to CA1 region of the hippocampus | |
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NR1 expression lost two weeks post natal | |
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mice are viable and develop normally | |
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short-term potentiation (STP), long-term potentiation (LTP) or long-term depression (LTD) cannot be induced in CA1 neurons | |
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LTP can be induced in the dentate gyrus | |
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deficient in spatial memory (hidden platform in Morris water maze) | |
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decreased specificity of individual CA1 neuronal place fields | |
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deficit in the co-ordinated firing of pairs of neurones tuned to similar place fields | |
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deficit in relational memory - the ability to associate odour pairs with rewards where a single odour leads to a reward when associated with a specific second odour | |
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Olfactory perception and the ability to associate specific odours with specific rewards is unimpaired | |
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Trafficking of NR2 subunits is disrupted in the CA1 region with NR2A and NR2B being retained in somatic ER | |
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a further mutant has been produced in which the knockout of NR1 expression in hippocampal CA1 neurones is placed under tetracyclin control (Tet-OFF) | |
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this mutant shows a deficit in both spatial and contextual fear momory consolidation when NR1 expression is switched off by treatment with doxycyclin (dox) soon after the initial learning | |
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no effect on memory consolidation is seen when NR1 expression in maintained for 7 days following initial learning | |
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disruption of remote contextual and cued fear memories by prolonged NR1 downregulation (30 days) 6 months after initial learning | |
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no effect of short NR1 down-regulation (7 days) on remote contextual and cued fear memories | |
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a lack of LTP in entorhinal neurones following dox treatment for 5 days in 8-11 month old mice | |
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Tsien J.Z., Huerta P.T. and Tonegawa S. (1996) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory Cell 87; 1327-1338 [Medline] McHugh T.J., Blum K.I., Tsien J.Z., Tonegawa S. and Wilson M.A. (1996) Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mouse. Cell 87; 1339-1349 [Medline] Rondi-Reig L., Libbey M., Eichenbaum H. and Tonegawa S. (2001) CA1-specific N-methyl-D-aspartate receptor knockout mice are deficient in solving a nonspatial transverse patterning task. PNAS USA 98; 3543-3548 [Medline] Fukaya M., Kato A., Lovett C., Tonegawa T., and Watanabe M. (2003) Retention
of NMDA receptor NR2 subunits
in the Shimizu E., Tang., Rampon C. and Tsien J.Z. (2000) NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 290; 1170-1174 [Medline] Cui Z., Wang H., Tan Y., Zaia K.A., Zhang S. and Tsien J.Z. (2004) Inducible
and Reversible NR1 Knockout
Reveals Crucial Role of the NMDA Receptor
in Preserving Remote Memories in the Brain. Neuron 41; 781-793 [Medline]
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4) |
NR1 conditional knockout - hippocampal CA3 deletion |
Last updated: 18th
February 2003
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generated by cre-loxP recombination (cre expression driven by the regulatory sequences of the KA-1 gene) | |
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loss of NR1 expression is restricted to CA3 region of the hippocampus | |
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mice are viable and develop normally |
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NR1 deletion in pyramidal cells begins at five weeks post natal and reaches near completion at eighteen weeks post natal | |
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NR1 expression in CA1 pyramidal cells and general hippocampal architecture is normal | |
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NMDAR-dependent LTP in C/A-CA3 synapses is essentially absent, but NMDAR-independent LTP in MF-CA3 synapses is normal | |
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LTP in SC-CA1 synapses is normal | |
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spatial memory is normal (cued hidden platform in Morris water maze) | |
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deficit in pattern completion, assessed by removing three out of four cues (partial cue conditions) in the hidden platform test (less time spent at the recalled platform site). | |
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individual CA1 neuronal place fields are normal under full-cue conditions, although complex burst spike frequency and complex spike index of CA1 pyramidal cells are reduced | |
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co-ordinated firing of pairs of CA1 neurones tuned to similar place fields is normal under full cue conditions | |
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deficit in burst spike frequency, place field size and co-ordinated firing of CA1 neurones under partial cue conditions | |
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Nakazawa K., Quirk M.C., Chitwood R.A., Watanabe M., Yeckel M.F., Sun L.D., Kato A., Carr C.A., Johnston D., Wilson M. and Tonegawa S. (2002) Requirement of hippocampal CA3 NMDA receptors in associative memory recall. Science 297; 211-218 [Medline] |
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4) |
NR1 conditional knockout - cortical deletion |
Last updated: 21st
February 2003
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generated by cre-loxP recombination (cre expression driven by the regulatory sequences of the homeobox gene, Emx1) | |
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mice are viable but develop more slowly than control littermates (70% of the body weight of littermates at P7) | |
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loss of NR1 expression is restricted to excitatory neurones in cortical regions, including the somatosensory barrel cortex and the hippocampus at P7 |
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absence of NMDA receptor-mediated excitation in the barrel cortex; AMPA receptor-mediated excitation is normal | |
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whisker development and neural pattern in the brain-stem, dorsal column nuclei and the ventrobasal thalamus in normal | |
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small and indistict barrels patterns formed in the barrel cortex, patches due to the bundles of thalamocortical axons | |
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barrel cortex cell numbers are unaltered, but no barrel boundaries are formed (uniform granule cell distribution) | |
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patterns related to sinus hairs and digits are mostly absent | |
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thalamocortical axons (TCA) undergo normal structural plasticity in response to whisker lesion | |
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dendtritic fields of spiny stellate cells do not orient towards TCA terminal patches, but radiate in all directions | |
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dendritic fields of spiny stellate cells show profuse branching and increased spine density | |
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TCA terminal branching is poorly developed | |
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thus, cortical NMDAR activation is necessary in the transfer of periphery-related patterns to the cortex | |
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Iwasato T., Datwani A., Wolf A.M., Hiroshi N., Tagichi Y., Tonegawa S.,Knopfel T., Erzurumlu R.S. and Hohara S. (2000) Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 406; 726-731 [Medline] Datwani A., Iwasato T., Itohara S. and Erzurumlu R.S. (2002) Lesion-induced thalamocortical axonal plasticity in the S1 cortex is independent of NMDA receptor function in excitatory cortical neurons. J. Neurosci. 22; 9171-9175 [Medline] Datwani A., Iwasato T., Itohara S. and Erzurumlu R.S. (2002) NMDA receptor-dependent pattern transfer from afferents to post-synaptic cells and dendritic differentiation in the barrel cortex. MCN 21; 477-492 [Medline] |
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5) |
NR1 N598 Mutants |
Last updated: 18th
February 2003
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multiple lines generated replacing asparagine 598 (N598) with glutamine (Q) or arginine (R) | |
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generated by homologous recombination in ES cells | |
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expression of mutant alleles is 'silenced' by presence of a 'floxed' neomycin resistance sequence (neo) | |
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neo gene removed either in vitro (Cre recombinase expressed in ES cells) or in vivo (silent mutant mice crossed with Cre-deleter mice) | |
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expression of pure mutant NR1 (either N598Q or N598R) is lethal within 1 hour of birth (resipratory deficits, lack of suckling response; cf global NR1 knockout) | |
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silencing of either mutation (through retention of the neo sequence) converts the phenotype to that of the NR1 knockout (lethal within 10 hours of birth) | |
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heterozygotes for either mutation exhibit increased mortality but more severe for N598R mutation |
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heterozygotes expressing silenced mutations are phenotypically indistinguishable from wild-type mice | |
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homozygotic N598Q mice show a four-fold reduction in calcium permeability | |
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homozygotic N598Q mice show incomplete magnesium block (and thus increased ion flux) at resting membrane potentials; | |
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homozygotic N598Q mice show a strong, voltage-dependent calcium block that is dominant over usual magnesium block at depolarising potentials | |
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NMDA receptor complexes with both native and N598Q mutant subunits show functional characteristics of native receptors | |
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NMDA receptor-dependent LTP in CA1 hippocampal neurons is normal in N598Q heterozygotes | |
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N598Q heterozygotes show impaired maternal behaviour | |
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NMDA receptor currents are undetectable in hemizygotic N598R mice (only one (mutant) allele is expressed) | |
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N598R mutant subunit is functionally dominant over native NR1 subunits within mixed receptors | |
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heterozygotic N598R mutant mice show normal somatosensory map formation in the brain stem | |
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further mutants utilizing the Tet-off expression system linked to the alpha-CAMKII promoter controlled expression of the transgene in a normal background | |
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expression of the transgene in the absence of doxycycline is highest in the forebrain and not detectable in the cerebellum or brainstem | |
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transgene expression in mice in which the mother did not receive doxycycline during pregnancy was lethal within 22-28 days | |
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transgene expression in mice in which the mother received doxycline up to birth was generally reduced and was completely absent in the hippocampus | |
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mice in which transgene expression was suppressed during embryonic development and at up to P10 were phenotypically normal | |
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Calcium permeability is impaired in 69% of olfactory bulb granule cells | |
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Single F.N., Rozov A., Burnashev N., Zimmermann F., Hanley D.F., Forrest D., Curran T., Jensen V., Hvalby O., Sprengel R. and Seeburg P.H. (2000) Dysfunctions in mice by NMDA receptor point mutations NR1(N598Q) and NR1(N598R). J. Neurosci. 20; 2558-2566 [Medline] Jerecic J., Schulze C.H., Jonas P., Sprengel R.,
Seeburg P.H. and Bischofberger J. (2001) Imparied NMDA receptors function
in mouse olfactory bulb neurones by teracycline-sensitive NR1 (N589R)
expression. Mol. Brain Res. 94; 96-104 [Medline]
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NMDAR2 Subunit Transgenic Mice
The expression of all four NMDA receptor subunits NR2A-D have been modified. In addition to the generation of knockout mice, in which the expression of the subunits have been lost, both NR2B and NR2D have been over-expressed. Mutanat receptor subunits with C-terminal deletions of NR2A-C have also been expressed, replacing the native subunits. Studies such as these have demonstrated that correct expression of the NR2B subunit is essential to neonatal survival and somatosensory map formation (cf NR1). Deletion studies have shown that the C-terminus of the NR2B subunit is important in the synaptic targetting of the NMDA receptor complex. In addition to this, over-expression of either NR2B or NR2D results in NMDA receptors with characteristics found in juvenile animals. It is interesting that both these receptor subunits undergo developmental down-regulation - NR2B is expressed at higher levels in juvenile animals while NR2D is expressed primarily during embryonic development. In behavioural tests, over-expression of NR2B appears to enhace the ability to retain information leading to better long-term memory whereas over-expression of NR2D retards the development of induced epileptic seizures, suggesting a role for this receptor subunit in the development of epilepsy. |
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1)
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NR2A global knockout | Last updated:
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generated by homolgous recombination in ES cells | |
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NR2A expression lost thoughout the brain | |
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overall neuroanatomy normal | |
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reduced NMDA receptor-mediated component of synaptic transmission in hippocampus (CA1) | |
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reduced induction of LTP in hippocampus (CA1; stratum radiatum and stratum oriens) and cerebellum | |
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reduced synaptic transmission and LTP induction in associational input to hippocampal CA3 neurons (stratum radiatum) | |
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no effect on synaptic transmission or LTP in fimbrial inputs (stratum oriens) to same cells (cf NR2B knockout) | |
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LTP deficits are overcome by giving a stronger tetanus | |
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mice show deficits in Morris water maze learning, eyeblink response and associative learning | |
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complete C-terminal deletion produces similar effects on LTP | |
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Sakimura K., Kutsuwada T., Ito I., Manabe T., Takayama C., Kushiya E., Yagi T., Aizawa S., Inoue Y., Sugiyama H and Mishina M. (1995) Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor e1 subunit. Nature 373; 151-155 [Medline][TBase] Kadotani H., Hirano T., Masugi M., Nakamura K., Nakao K., Katsuki M. and Nakanishi S. (1996) Motor discoordination results from the combined gene disruption of the NMDA receptor NR2A and NR2C subunits, but not from single disruption of the NR2A or NR2C subunit. J. Neurosci. 16; 7859-7867 [Medline] Ito I., Futai K., Katagiri H., Watanabe M., Sakimura K., Mishina M and Sugiyama H. (1997) Synapse-selective impairment of NMDA receptor functions in mice lacking NMDA receptor e1 or e2 subunits. J. Physiol. (Lond) 500.2; 401-408 [Medline] Kiyama Y., Manabe T., Sakimura K., Kawakami F., Mori H and Mishina M. (1998) Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor e1 subunit. J. Neurosci. 18; 6704-6712 [Medline] Kishimoto Y., Kawahara S., Kirino Y., Kadotani H., Nakamura Y., Ikeda M. and Yoshioka T. (1997) Conditioned eyeblink response is impaired in mutant mice lacking NMDA receptor subunit NR2A. Neuroreport 8; 3717-3721 [Medline] Sprengel R., Suchanek B., Amico C., Brusa R., Burnashev N., Rozov A.,
Hvalby O., Jensen V., Paulsen O., Andersen P., Kim J.J., Thompson R.F.,
Sun W., Webster L.C., Grant S.G., Eilers J., Konnerth A., Li J., McNamara
J.O. and Seeburg P.H. (1998) Importance of the intracellular domain of
NR2 subunits for NMDA receptor function in vivo. Cell 92; 279-289
[Medline]
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2) |
NR2B global knockout |
Last updated: 20th
February 2003
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generated by homolgous recombination in ES cells |
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subunit is essential for neonatal survival (cf NR1 global knockout), but overall neuroanatomy is normal | |
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complete loss of whisker-related patterns ('barrels') in the brainstem | |
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LTD cannot be induced in CA1 hippocampal neurons | |
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LTP in fimbrial input to CA3 neurons is severely impaired in heterozygotes (cf NR2A knockout) | |
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heterozygotes show increased acoustic startle response (ASR) and a slight increase in prepulse inhibition of ASR | |
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no effect on ASR seen with homozygous NR2A,C or D kcockouts | |
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Kutsuwada T., Sakimura K., Manabe T., Takayama C., Katakura N., Kushiya E., Natsume R., Watanabe M., Inoue Y., Yagi T., Aizawa S., Arakawa M., Takahashi T., Nakamura Y., Mori H. and Mishina M. (1996) Impairment of suckling response, trigeminal neuron pattern formation, and hippocampal LTD in NMDA receptor e2 subunit mutant mice. Neuron 16; 333-344 [Medline] Ito I., Futai K., Katagiri H., Watanabe M., Sakimura K., Mishina M and Sugiyama H. (1997) Synapse-selective impairment of NMDA receptor functions in mice lacking NMDA receptor e1 or e2 subunits. J. Physiol. (Lond) 500.2; 401-408 [Medline] Takeuchi T., Kiyama Y., Nakamura K., Tsujita M., Matsuda I., Mori H., Munemoto Y., Kuriyama H., Natsume R., Sakimura K. and Mishina M. (2001) Roles of the glutamate receptor epsilon2 and delta2 subunits in the potentiation and prepulse inhibition of the acoustic startle reflex. Eur. J. Neurosci. 14; 153-160 [Medline] |
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3) |
NR2 C-terminal deletion knock-ins |
Last updated: 21st
February 2003
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generated by homolgous recombination in ES cells | |
| NR2B | ||
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deletion of the entire C-terminus is lethal prenatally (Sprengel et al,1998) | |
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deletion of two-thirds of the C-terminus results in mice that are viable up to postnatal day three | |
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disrupted barrel formation in the brainstem | |
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LTP can be induced in some CA1 hippocampal neurons (cf NR2B global knockout) | |
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reduced synaptic expression of NR2B subunit but the number of synapses in normal | |
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in embryonic neocortical neurons from homozygous mice, NMDA receptor-mediated EPSCs show a reduced peak amplitude and mean open probability | |
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severe reduction in the fraction of NMDA receptrs that are synaptically localised | |
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synaptic localization recovers with increasing time in culture as receptors containing NR2A are expressed | |
| NR2A/C | ||
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marked reduction in NMDA receptor-mediated EPSC at the cerebellar mossy-fibre-granule cell relay | |
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no effect of neurotransmitter release | |
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no effect on NMDA receptor development or expression pattern | |
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reduced peak open probability in synaptic NMDA channels | |
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impaired NMDA receptor-dependent LTP | |
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Mori H., Manabe T., Watanabe M., Satoh Y., Suzuki N., Toki S., Nakamura K., Yagi T., Kushiya E., Takahashi T., Inoue Y., Sakimura K. and Mishina M. (1998) Role of the carboxy-terminal region of the GluRe2subunit in synaptic localization of the NMDA receptor channel. Neuron 21; 571-580 [Medline] Sprengel R., Suchanek B., Amico C., Brusa R., Burnashev N., Rozov A., Hvalby O., Jensen V., Paulsen O., Andersen P., Kim J.J., Thompson R.F., Sun W., Webster L.C., Grant S.G., Eilers J., Konnerth A., Li J., McNamara J.O. and Seeburg P.H. (1998) Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92; 279-289 [Medline] Rossi P., Sola E., Taglietti V., Borchardt T., Steigerwald F., Utvik J.K., Otterson O.P., Kohr G. and D'Angelo E. (2002) NMDA receptor 2 (NR2) C-terminal control of NR open probability regulates synaptic transmission and plasticity at a cerebellar synapse. J. Neurosci. 22; 9687-9689 [Medline] Mohrmann R., Kohr G., Hatt H., Sprengel R. and Gottmann K. (2002) Deletion
of C-terminal domain of the NR2B subunit alters channel properties and
synaptic targeting of N-methyl-D-aspartate receptors in nascent neocortical
synapses. J. Neurosci. Res. 68; 265-275 [Medline]
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4) |
NR2B knock-in |
Last updated: 20th
February 2003
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generated by pronuclear injection | |
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NR2B subunit is overexpressed by linkage to the CaMKII promoter, producing overexpression in the forebrain | |
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overall neuroanatomy and development is normal | |
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NMDA receptor-mediated synaptic currents are similar to those in juvenile mice (slow kinetics) from 18 days post natal (Note: NR2B undergoes a developmental down-regulation - cf NR2D knock-in) | |
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LTP induced by tetani in the 10-100 Hz range is enhanced in CA1 neurons | |
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LTD and paired pulse facilitation is normal | |
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better long term visual recognition memory that can be further enhanced by rearing animals in an enriched environmemt, but no effect on plasticity at the synpatic level in the visual cortex | |
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stronger freezing responses in contextual and cued fear conditioning | |
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enhanced ability to dissociate fear responses from contextual and tonal cues | |
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faster spatial learning in Morris water maze | |
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no further increases in contextual and cued fear conditioning responses or fear extinction when raised in an enriched environment | |
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enhanced NMDA receptor mediated fEPSP in anterior cingulate cortex and insular cortex (areas involved in processing of pain-related information) | |
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no effect on fEPSPs or any transgene expression found in dorsal horn | |
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selective increase in c-fos expression in response to tissue injury/inflammation in areas with enhanced NR2B expression | |
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enhanced display of a withdrawal response to a previously non-noxious stimulus | |
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enhanced odour memory function | |
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Tang Y-P., Shimizu E., Dube G.R., Rampon C., Kerchner G.A., Zhuo M., Liu G., Tsien J.Z. (1999) Genetic enhancement of learning and memory in mice. Nature 401; 63-69 [Medline] Philpot B.D., Weisberg M.P., Ramos M.S., Satwell N.B., Tang Y-P. and Bear M.F (2001) Effect of transgenic overexpression of NR2B on NMDA receptor function and synaptic plasticity in the visual cortex. Neuropharmacology 41; 762-770 [Medline] Tang Y-P., Wang H., Feng R., Kyin M. and Tsein J.Z. (2001) Differential effects of enrichment on learning and memory function in NR2B transgenic mice. Neuropharmacology 41; 779-790 [Medline] Wei F., Wang G.D., Kerchner G.A., Kim S.J., Xu H-M, Chen Z-F. and Zhuo M. (2001) Genetic ehnancement of imflammatory pain by forebrain NR2B overexpression. Nature Neuroscience 4; 164-169 [Medline] White T.L. and Youngentob S.L. (2004) The effect of NMDA-NR2B receptor
subunit over-expression on olfactory
memory task performance in the mouse. Brain Res. 1021; 1-7. [Medline]
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5) |
NR2C global knockouts |
Last updated:
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two strains generated by homolgous recombination in ES cells | |
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first strain shows reduced NMDA receptor-mediated component of cerebellar granule cell EPSC | |
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second strain shows a higher EPSC peak amplitude but shorter decay time than in wild-type mice | |
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Low conductance channels are also lost (channels with conductance below 37 pS) | |
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no motor impairments have been seen with single NR2C gene knockouts | |
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mice with combined gene deletions of NR2A and NR2C can only manage simple co-ordination tasks | |
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Kadotani H., Hirano T., Masugi M., Nakamura K., Nakao K., Katsuki M. and Nakanishi S. (1996) Motor discoordination results from the combined gene disruption of the NMDA receptor NR2A and NR2C subunits, but not from single disruption of the NR2A or NR2C subunit. J. Neurosci. 16; 7859-7867 [Medline] Ebralidze A.K., Rossi D.J., Tonegawa S. and Slater N.T. (1996) Modification of NMDA receptor channels and synaptic transmission by targeted disruption of the NR2C gene. J. Neurosci. 16; 5014-5025 [Medline] |
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6) |
NR2D global knockout |
Last updated: 20th
February 2003
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generated by homolgous recombination in ES cells | |
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minimal effects - NR2D is expressed at it's highest levels during embryonic and early postnatal stages of development | |
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neuroanatomy is normal | |
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motor and anxiety responses are normal | |
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spontaneous activity in the open field is reduced | |
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expression of NR2A and B subunits is normal | |
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specific binding of MK-801 to the NMDA receptor in adults is reduced | |
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uptake of calcium through in response to pharmacological activation of the NMDA receptor is reduced but is unaffected by high K+ stimulation in adults | |
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altered monoaminergic neuronal function (dopaminergic, setotoninergic, nor-adrenergic) | |
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reduced locomotion and rearing behaviour | |
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mice may have a reduced susceptibility to stress and/or reduced psychological anxiety (elevated maze, light-dark box and forced swimming tests) | |
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Ikeda K., Araki K., Takayama C., Inoue Y., Yagi T., Aizawa S. and Mishina M. (1995) Reduced spontaneous activity of mice defective in the e4 subunit of the NMDA receptor channel Mol. Brain Res. 33; 61-75 [Medline] Miyamoto Y., Yamada K., Noda Y., Mori H., Mishina M. and Nabeshima T (2002) Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA recepor epsilon4 subunit. J. Neurosci. 22; 2335-2342 [Medline] |
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|
7) |
NR2D global knock-in |
Last updated:
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generated by pronuclear injection | |
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NR2D subunit is overexpressed by linkage to the CaMKII promoter | |
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overall neuroanatomy and barrel formation is normal | |
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selective expression of NR2D in cortex, hippocampus and striatum reaching maximum by 8 weeks (adult) | |
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lower amplitude and slower kinetics of evoked currents in hippocampal CA1 cells from adult mice (cf NR2B subunit knockin) | |
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impaired LTD in juvenile mice in hippocampal CA1 cells ; no effect on LTP | |
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impaired LTP in adult mice in hippocampal CA1 cells; LTD not induced in either mutant or wild-type mice | |
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spatial memory is normal (Morris water maze) but mutants are less motile and show reduced exploratory behaviour in the open field | |
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supression of kindling epileptogenesis (retarded development of motor seizure and afterdischarge duration) | |
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no effect on pre-established epileptic seizures |
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Okabe S., Collin C., Auerbach J.M., Meiri N., Bengzon J., Kennedy M.B., Segal M. and McKay R.D. (1998) Hippocampal synaptic plasticity in mice overexpressing an embryonic subunit of the NMDA receptor. J. Neurosci. 18; 4177-4188 [Medline] Bengzon J., Okabe S., Lindvall O. and McKay R.D.G. (1999) Suppression
of epileptogenesis by modification of N-methyl-D-aspartate receptor subunit
composition. Eur. J. Neurosci. 11; 916-922 [Medline]
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| NMDAR3 Subunit Knockout
Mice
The NMDA receptor subunit NR3A is a recently characterised subunit (also known as c-1 and NMDAR-L) that is expressed primarily during brain development and has also been shown to exist in complexes with NR1 and NR2 subunits. Little is yet known about the function of this subunit, but from work with the only knockout mouse described, it appears to be a regulatory subunit involved in dendritic spine development. |
|
1)
|
NR3A global knockout | Last updated:
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generated by homolgous recombination in ES cells | |
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no obvious behavioural abnormalities | |
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normal levels of other NMDA receptor subuhnits | |
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|
three-fold increase in NMDA-induced current density in acutely dissociated cerebrocortical neurons | |
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three to four-fold increase in dendritic spine density on both basal and apical dendrites of cortical neurons from layers IV and V in P19 mice | |
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increased size of spine head and increased length of spine neck | |
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no effects seen in cerebellar purkinje cells, which do not express the NR3A subunit | |
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Das S., Sasaki Y.F., Rothe T., Premkumar L.S., Takasu M., Crandall J.E.,
Dikkes P., Conner D.A., Rayudu P.V., Cheung W., Cheung H-S.V., Lipton
S.A., Nakanishi N. (1998) Increased NMDA current and spine density in
mice lacking the NMDA receptor subunit NR3A. Nature 393; 377-381
[Medline]
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