Developmental and regional expression in the rat brain and functional properties of four NMDA receptors

Monyer, Hannah; Burnashev, Nail; Laurie, David J.; Sakmann, Bert; Seeburg, Peter H.

doi:10.1016/0896-6273(94)90210-0

Cited by 3,211 publications

(3,140 citation statements)

References 31 publications

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“…When directly comparing the neuroprotective effects of EPO and CEPO on the CA3 and CA1 pyramidal and dentate granule cells layers tested in the two lesion models (OGD and NMDA), CEPO was significantly more efficient for all cell layers in the OGD experiments, but did not reach significant difference from EPO in any of the subfields in the NMDA experiments. In the NMDA lesion model, where CA1 pyramidal cells have been shown to be more susceptible to NMDA excitotoxicity than other hippocampal neurons (Monyer et al, 1994), we observed Fig. 7.…”

Section: Discussionmentioning

confidence: 68%

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Montero

Poulsen

Noraberg

et al. 2007

Experimental Neurology

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In addition to its well-known hematopoietic effects, erythropoietin (EPO) also has neuroprotective properties. However, hematopoietic side effects are unwanted for neuroprotection, underlining the need for EPO-like compounds with selective neuroprotective actions. One such compound, devoid of hematopoietic bioactivity, is the chemically modified, EPO-derivative carbamylerythropoietin (CEPO). For comparison of the neuroprotective effects of CEPO and EPO, we subjected organotypic hippocampal slice cultures to oxygen-glucose deprivation (OGD) or N-methyl-D-aspartate (NMDA) excitotoxicity. Hippocampal slice cultures were pretreated for 24 h with 100 IU/ml EPO (= 26 nM) or 26 nM CEPO before OGD or NMDA lesioning. Exposure to EPO and CEPO continued during OGD and for the next 24 h until histology, as well as during the 24 h exposure to NMDA. Neuronal cell death was quantified by cellular uptake of propidium iodide (PI), recorded before the start of OGD and NMDA exposure and 24 h after. In cultures exposed to OGD or NMDA, CEPO reduced PI uptake by 49 ± 3 or 35 ± 8%, respectively, compared to lesion-only controls. EPO reduced PI uptake by 33 ± 5 and 15 ± 8%, respectively, in the OGD and NMDA exposed cultures. To elucidate a possible mechanism involved in EPO and CEPO neuroprotection against OGD, the integrity of α-II-spectrin cytoskeletal protein was studied. Both EPO and CEPO significantly reduced formation of spectrin cleavage products in the OGD model. We conclude that CEPO is at least as efficient neuroprotectant as EPO when excitotoxicity is modeled in mouse hippocampal slice cultures.

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Section: Discussionmentioning

confidence: 68%

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Montero

Poulsen

Noraberg

et al. 2007

Experimental Neurology

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“…The functional significance of this unique NR1/ NR2C assembly is not understood at present and further studies are needed to elucidate its physiological relevance in the human LC. However, based on the previous observations, recombinant NR1/2C receptors have a lower current amplitude, shorter open time, smaller single conductance, and reduced sensitivity to Mg 2 þ than other subunit assemblies (Daggett et al, 1998;Ishii et al, 1993;Kutsuwada et al, 1992;Laurie and Seeburg, 1994;Monyer et al, 1994).…”

Section: Nmdar Subunit Composition In the Human Lcmentioning

confidence: 96%

Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Karolewicz

Stockmeier

Ordway

2005

Neuropsychopharmacol

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Low levels of the intracellular mediator of glutamate receptor activation, neuronal nitric oxide synthase (nNOS) were previously observed in locus coeruleus (LC) from subjects diagnosed with major depression. This finding implicates abnormalities in glutamate signaling in depression. Receptors responding to glutamate in the LC include ionotropic N-methyl-D-aspartate receptors (NMDARs). The functional NMDAR is a hetero-oligomeric structure composed of NR1 and NR2 (A-D) subunits. Tissue containing the LC and a nonlimbic LC projection area (cerebellum) was obtained from 13 and 9 matched pairs, respectively, of depressed subjects and control subjects lacking major psychiatric diagnoses. NMDAR subunit composition in the LC was evaluated in a psychiatrically normal subject. NR1 and NR2C subunit immunoreactivities in LC homogenates showed prominent bands at 120 and 135 kDa, respectively. In contrast to NR1 and NR2C, very weak immunoreactivity of NR2A and NR2B subunits was observed in the LC. Possible changes in concentrations of NR1 and NR2C that might occur in depression were assessed in the LC and cerebellum. The overall amount of NR1 immunoreactivity was normal in the LC and cerebellum in depressed subjects. Amounts of NR2C protein were significantly higher ( þ 61%, p ¼ 0.003) in the LC and modestly, but not significantly, elevated in the cerebellum ( þ 35%) of depressives as compared to matched controls. Higher levels of NR2C subunit implicate altered glutamatergic input to the LC in depressive disorders.

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“…2,3 On the other hand, NMDAR hypofunction is also implicated in other pathologies such as schizophrenia. 4 The receptors are hetero-oligomeric proteins formed by obligatory NR1 subunits 5,6 interacting with NR2A-D, conferring functional variability. 7,8 The major NR2 subunits in adult neocortex and hippocampus are NR2A and NR2B.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 The major NR2 subunits in adult neocortex and hippocampus are NR2A and NR2B. Although they are not exclusive locations, 9 NR2A is predominantly confined to synapses of mature neurons 5 while NR2B is distributed mainly extrasynaptically. [10][11][12] The synaptic NMDARs form large and dynamic signaling complexes in the postsynaptic membrane, 13 mainly by interaction of their intracellular NR2 C terminus with additional proteins such as postsynaptic density-95 (PSD-95), which functions as a scaffolding and organizer protein of the PSD.…”

Section: Introductionmentioning

confidence: 99%

Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95

et al. 2007

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The N-methyl-D-aspartate receptor (NMDAR) is central to physiological and pathological functioning of neurons. Although promising results are beginning to be obtained in the treatment of dementias, clinical trials with NMDAR antagonists for stroke, trauma and neurodegenerative disorders, such as Hungtinton's disease, have failed before. In order to design effective therapies to prevent excitotoxic neuronal death, it is critical to characterize the consequences of excessive NMDAR activation on its expression and function. Previous data have reported partial downregulation of the NR1 and NR2B receptor subunits in response to excitotoxicity and cerebral ischemia. However, the effect of NMDAR overactivation on NR2A, a subunit fundamental to synaptic transmission and neuronal survival, is still elusive. In this study, we report the rapid and extensive proteolytic processing of NR2A, together with the scaffolding protein postsynaptic density-95 (PSD-95), induced by excitotoxic stimulation of cortical neurons in vitro and by transient focal cerebral ischemia. Processing of the C terminus of NR2A is irreversibly induced by brief agonist exposure of NR2B-containing receptors, and requires calcium influx and the activity of calpain, also responsible for PSD-95 cleavage. The outcome is a truncated NR2A subunit that is stable and capable to interact with NR1 at the surface of neurons, but lacking the structural domains required for association with scaffolding, downstream signaling and cytoskeletal proteins. Therefore, a rapid and significant uncoupling of synaptic NMDARs from downstream survival pathways is expected to occur during ischemia. This novel mechanism induced by excitotoxicity helps to explain the failure of most therapies based on NMDAR antagonists.

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Developmental and regional expression in the rat brain and functional properties of four NMDA receptors

Cited by 3,211 publications

References 31 publications

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Elevated Levels of the NR2C Subunit of the NMDA Receptor in the Locus Coeruleus in Depression

Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95

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