Motor Discoordination Results from Combined Gene Disruption of the NMDA Receptor NR2A and NR2C Subunits, But Not from Single Disruption of the NR2A or NR2C Subunit

Kadotani, Hiroshi; Hirano, Tomoo; Masugi, Miwako; Nakamura, Kenji; Nakao, Kazuki; Katsuki, Motoya; Nakanishi, Shigetada

doi:10.1523/jneurosci.16-24-07859.1996

Cited by 175 publications

(144 citation statements)

References 33 publications

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“…In agreement with previous reports (Ebralidze et al, 1996;Ikeda et al, 1995;Kadotani et al, 1996), NR2C nlacZ null mice do not exhibit obvious altered behaviors. However, NMDAR-EPSC peak amplitudes and charge transfer are significantly increased at autaptic synapses of cerebellar granule cells isolated from NR2C nlacZ null mice (Lu et al, 2006), consistent with previous studies performed in slices from NR2 null mice (Ebralidze et al, 1996;Takahashi et al, 1996).…”

Section: Discussionsupporting

confidence: 93%

“…An intriguing possibility is that NR1 expression is upregulated in hippocampal astrocytes by ischemia or anoxia, as previously reported (Krebs et al, 2003). Consistent with the idea that functional NR2C-containing NMDARs may be expressed in response to ischemia, cerebral vascular occlusion selectively increases NR2C mRNA expression in vulnerable areas (Small et al, 1997) and mutation of the NR2C gene reduces ischemic injury in mice (Kadotani et al, 1996). Interestingly, we observed that NR2C-nβ-gal expression is highest in CA1 and subiculum, as compared to the dentate, which coincides with regions most susceptible to global ischemic damage.…”

Section: Expression Of the Nr2c In Non-neuronal Cellssupporting

confidence: 67%

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Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-β-galactosidase knock-in mice

Karavanova

Vasudevan

Cheng

et al. 2007

Molecular and Cellular Neuroscience

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NMDA receptor "knock-in" mice were generated by inserting the nuclear β-galactosidase reporter at the NR2C subunit translation initiation site. Novel cell-types and dynamic patterns of NR2C expression were identified using these mice, which were unnoticed before because reagents that specifically recognize NR2C-containing receptors are non-existent. We identified a transition zone from NR2C-expressing neurons to astrocytes in an area connecting the retrosplenial cortex and hippocampus. We demonstrate that NR2C is expressed in a subset of S100β-positve/GFAP-negative glial cells in the striatum, olfactory bulb and cerebral cortex. We also demonstrate novel areas of neuronal expression such as retrosplenial cortex, thalamus, pontine and vestibular nuclei. In addition, we show that during cerebellar development NR2C is expressed in transient caudalrostral gradients and parasagittal bands in subsets of granule cells residing in the internal granular layer, further demonstrating heterogeneity of granule neurons. These results point to novel functions of NR2C-containing NMDA receptors.

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Section: Discussionsupporting

confidence: 93%

Section: Expression Of the Nr2c In Non-neuronal Cellssupporting

confidence: 67%

Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-β-galactosidase knock-in mice

Karavanova

Vasudevan

Cheng

et al. 2007

Molecular and Cellular Neuroscience

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“…The GluR⑀3-KO and GluR⑀1/⑀3-KO mice were viable, grew normally, and were fertile. However, the GluR⑀1/⑀3-KO mouse showed mild impairment in motor coordination when tested on the rotating rod at high speeds (data not shown), as reported previously (Ebralidze et al, 1996;Kadotani et al, 1996).…”

Section: Production Of Glur⑀1/⑀3-ko Micesupporting

confidence: 86%

“…The most notable change emerged in the immunochemical visibility of the GluR1 subunit in the cerebellar granular layer. The order of immunohistochemical loss is grossly parallel with that in a previous electrophysiological study in which NMDA receptormediated currents are significantly reduced in granule cells lacking the GluR⑀1 or GluR⑀3 subunit, and almost absent in those lacking both subunits (Kadotani et al, 1996). The loss of the GluR1 subunit is attributable to neither transcriptional and translational downregulations nor to abnormal cellular and synaptic differentiations of granule cells.…”

Section: Discussionsupporting

confidence: 74%

NMDA Receptor GluRϵ/NR2 Subunits Are Essential for Postsynaptic Localization and Protein Stability of GluRζ1/NR1 Subunit

Abe¹,

Fukaya²,

Yagi³

et al. 2004

J. Neurosci.

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In NMDA receptors, GluR⑀/NR2 subunits strictly require the GluR1/NR1 subunit to exit from endoplasmic reticulum (ER) to the cell surface in vitro and to the postsynapse in vivo, whereas C terminus-dependent self-surface delivery has been demonstrated for the GluR1 subunit in vitro. To test whether this leads to C terminus-dependent self-postsynaptic expression in neurons in vivo, we investigated the GluR1 subunit in cerebellar granule cells lacking two major GluR⑀ subunits, GluR⑀1/NR2A and GluR⑀3/NR2C. In the mutant cerebellum, synaptic labeling for the GluR1 subunit containing the C2 (GluR1-C2) or C2Ј (GluR1-C2Ј) cassette was reduced at mossy fiber-granule cell synapses to the extrasynaptic level. The loss was not accompanied by decreased transcription and translation levels, increased extrasynaptic labeling, or ER accumulation. Quantitative immunoblot revealed substantial reductions in the mutant cerebellum of GluR1-C2 and GluR1-C2Ј. The most severe deficit was observed in the postsynaptic density (PSD) fraction: mutant levels relative to the wild-type level were 12.3 Ϯ 3.3% for GluR1-C2 and 17.0 Ϯ 4.6% for GluR1-C2Ј. The GluR1 subunit carrying the C1 cassette (GluR1-C1) was, although low in cerebellar content, also reduced to 12.7 Ϯ 3.5% in the mutant PSD fraction. Considering a trace amount of other GluR⑀ subunits in the mutant cerebellum, the severe reductions thus represent that the GluR1 subunit, by itself, is virtually unable to accumulate at postsynaptic sites, regardless of C-terminal forms. By protein turnover analysis, the degradation of the GluR1 subunit was accelerated in the mutant cerebellum, being particularly rapid for that carrying the C2 cassette. Therefore, accompanying expression of GluR⑀ subunits is essential for postsynaptic localization and protein stability of the GluR1 subunit.

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“…The goal of this study was to determine how decreasing the NR2A/B ratio alters the LTD/LTP m in vitro and compare this with changes in the properties of naturally occurring plasticity in the visual cortex in vivo as a consequence of MD. We examined this question using mice with targeted disruption of one or both alleles of the NR2A gene (19). Because NR2A mutant mice do not display compensatory alterations in NR1 or NR2B subunit expression in visual cortex at the ages of interest, reducing NR2A expression effectively changes the NR2A/B ratio (10).…”

Section: Resultsmentioning

confidence: 99%

The ratio of NR2A/B NMDA receptor subunits determines the qualities of ocular dominance plasticity in visual cortex

Cho

Khibnik

Philpot

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

101

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Bidirectional synaptic plasticity during development ensures that appropriate synapses in the brain are strengthened and maintained while inappropriate connections are weakened and eliminated. This plasticity is well illustrated in mouse visual cortex, where monocular deprivation during early postnatal development leads to a rapid depression of inputs from the deprived eye and a delayed strengthening of inputs from the non-deprived eye. The mechanisms that control these bidirectional synaptic modifications remain controversial. Here we demonstrate, both in vitro and in vivo, that genetic deletion or reduction of the NR2A NMDA receptor subunit impairs activity-dependent weakening of synapses and enhances the strengthening of synapses. Although brief monocular deprivation in juvenile WT mice normally causes a profound depression of the deprived-eye response without a change in the non-deprived eye response, NR2A-knockout mice fail to exhibit deprivation-induced depression and instead exhibit precocious potentiation of the non-deprived eye inputs. These data support the hypothesis that a reduction in the NR2A/B ratio during monocular deprivation is permissive for the compensatory potentiation of non-deprived inputs.metaplasticity ͉ synaptic homeostasis ͉ synaptic scaling ͉ visual evoked potential ͉ BCM theory T he circuitry of primary visual cortex is susceptible to changes in sensory experience during early postnatal development, as evidenced by the well studied paradigm of monocular deprivation (MD) (1). MD and reverse occlusion studies demonstrate that the strength of synapses is bidirectionally modifiable (2-4). A detailed time course of the synaptic events following MD in mice shows that the initial consequence is a rapid depression of the deprived-eye inputs followed by a delayed strengthening of the non-deprived eye inputs (5). However, little is known about the molecular mechanisms that regulate the susceptibility of synapses to bidirectional modifications in their strength.Bidirectional synaptic plasticity has been studied in slice recordings of visual cortex in the form of long-term potentiation (LTP) and long-term depression (LTD), whereby synapses strengthen and weaken in response to stimulation (6). These activity-dependent modifications can be modeled by a learning rule whereby high levels of post-synaptic activation (evoked electrically by high-frequency stimulation) induce LTP and smaller levels of post-synaptic activation (evoked electrically by lower-frequency stimulation) induce LTD (7). The crossover point from synaptic weakening to strengthening is called the modification threshold ( m ). An important feature of this model is that the value of m is not fixed; rather, its value can ''slide'' as a function of the history of post-synaptic activation. According to the BCM theory, closing the dominant contralateral eye first leads to depression of the deprived synapses, followed by a leftward shift in m caused by the reduction in average cortical activity. This shift in m is permissive for the subse...

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Motor Discoordination Results from Combined Gene Disruption of the NMDA Receptor NR2A and NR2C Subunits, But Not from Single Disruption of the NR2A or NR2C Subunit

Cited by 175 publications

References 33 publications

Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-β-galactosidase knock-in mice

Novel regional and developmental NMDA receptor expression patterns uncovered in NR2C subunit-β-galactosidase knock-in mice

NMDA Receptor GluRϵ/NR2 Subunits Are Essential for Postsynaptic Localization and Protein Stability of GluRζ1/NR1 Subunit

The ratio of NR2A/B NMDA receptor subunits determines the qualities of ocular dominance plasticity in visual cortex

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