Age dependent sensitivity of the rat retina to the excitotoxic action ofN-methyl-D-aspartate

Izumi, Yukitoshi; Kirby-Sharkey, Charity O.; Benz, Ann; Labruyere, Joann; Price, Madelon T.; Wozniak, David F.; Zorumski, Charles F.; Olney, John W.

doi:10.1006/nbdi.1995.0015

Cited by 14 publications

(12 citation statements)

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“…Since glutamatergic ribbon-synapses in the inner plexiform layer are formed around postnatal day 9 in the rat retina, it is attractive to speculate that NMDAR function is down-regulated after adult synaptic connectivity has been established. Such a developmental regulation of NMDA receptor function is also in accordance with the findings of Izumi et al (41), who showed that RGCs in rat retina explants are most sensitive to NMDA excitotoxicity at P9 and that from P15 on the sensitivity is strongly downregulated, remaining at a very low level in the adult.…”

Section: Developmental Regulation Of Nmdarsupporting

confidence: 91%

Developmental plasticity of NMDA receptor function in the retina and the influence of light

Guenther¹,

Schmid²,

Wheeler‐Schilling³

et al. 2004

FASEB j.

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Despite the early expression of NMDA receptors (NMDARs) in the retina, not much is known about their regulation and involvement in plasticity processes during retinal development and synapse formation. Here we report that NMDAR function in the inner retina is developmentally regulated and controlled by ambient light condition. A prominent down-regulation after eye opening of NMDAR function was observed in rat retinal ganglion cells (RGCs), which was prevented by dark rearing the animals for 1 month but was again induced by subsequent light exposure. As shown by molecular analysis of single RGCs, alterations in the subunit composition of NMDAR did not account for the light-dependent regulation of NMDAR function. Immunocytochemistry showed no differences in the NMDAR protein expression pattern between normal and dark-reared animals. In conclusion, our data clearly demonstrate that NMDAR function is modulated during periods of retinal plasticity independent of structural alterations in its subunit composition and thus different from mechanisms observed in higher visual centers.

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Section: Developmental Regulation Of Nmdarsupporting

confidence: 91%

Developmental plasticity of NMDA receptor function in the retina and the influence of light

Guenther¹,

Schmid²,

Wheeler‐Schilling³

et al. 2004

FASEB j.

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“…2000), suggesting that excitotoxicity was mostly mediated by polyamine binding to NMDA receptors. It has also been reported that the extent of NMDA damage is more severe in adult than in immature retinas (Izumi et al. 1995).…”

Section: Discussionmentioning

confidence: 94%

A role for polyamines in retinal ganglion cell excitotoxic death

Pernet¹,

Bourgeois²,

Polo³

2007

Journal of Neurochemistry

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Neuronal death due to excessive activation of N-methyl-D-aspartate (NMDA) receptors is a hallmark of neurodegenerative diseases. The polyamines: putrescine, spermine, and spermidine, bind to specific sites on the NMDA receptor and promote its activation, but their role in NMDA-induced neuronal death is ill defined. In this study, we characterized the role of polyamines in excitotoxic death of retinal ganglion cells (RGCs), a population of central neurons susceptible to NMDAinduced damage. Our data show that endogenous arginase I, the rate limiting enzyme for polyamine biosynthesis, is expressed in the intact, adult retina. Intraocular injection of NMDA visibly increased arginase I expression in Mü ller cells, the predominant glial cell-type in the mammalian retina. Inhibition of polyamine synthesis using di-fluoro-methyl-ornithine (DFMO) was markedly neuroprotective, while injection of exogenous polyamines in conjunction with NMDA exacerbated RGC death. Blockade of the polyamine binding sites on NMDA receptors using the non-competitive antagonist ifenprodil was neuroprotective, suggesting that polyamines contribute to excitotoxic death, at least partly, by binding to NMDA receptors. Importantly, we also demonstrate that NMDA leads to activation of both the Erk1/2 and PI3 K/Akt pathways, but only the PI3 K/Akt kinase was required for di-fluoro-methylornithine-induced RGC survival. In summary, our study reveals that polyamines modulate neuronal death in the retina via different mechanisms that potentiate NMDA-triggered excitotoxicity.

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“…This feature is of particular importance for vertebrate photoreceptors, cells that in darkness continuously discharge a neurotransmitter with potentially toxic properties (Olney et al, 1986; Izumi et al, 1995, 2003). Nevertheless, both sustained and graded release of glutamate is essential for conveying the visual message (Heidelberger, 2007).…”

Section: Discussionmentioning

confidence: 99%

Zinc modulation of calcium activity at the photoreceptor terminal: A calcium imaging study

Anastassov

Shen

Ripps

et al. 2013

Experimental Eye Research

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There is abundant experimental evidence that zinc ions (Zn2+) are present in the synaptic vesicles of vertebrate photoreceptors, and that they are co-released with glutamate. Here we show that increasing the concentration of extracellular zinc (2 μM to 2 mM) suppresses the entry of calcium into the synaptic terminals of isolated salamander double cones. The resultant dose-dependent curve was fit by an inverse Hill equation having an IC50 of 38 μM, and Hill coefficient of 1.1. Because there is currently no reliable way to measure the concentration of extracellular zinc, it is not known whether the zinc released under normal circumstances is of physiological significance. In an attempt to circumvent this problem we used zinc chelators to reduce the available pool of endogenous zinc. This enabled us to determine how the absence of zinc affected calcium entry. We found that when intra- or extra-cellular zinc was chelated by 250 μM of membrane-permeable TPEN or 500 μM of membrane-impermeable histidine, there was a significant rise in the depolarization-induced intracellular calcium level within photoreceptor terminals. This increase in internal [Ca2+] will undoubtedly lead to a concomitant increase in glutamate release. In addition, we found that blocking the L-type calcium channels that are expressed on the synaptic terminals of photoreceptors with 50 μM nicardipine or 100 μM verapamil abolished the effects of zinc chelation. These findings are a good indication that, when released in vivo, the zinc concentration is sufficient to suppress voltage-gated calcium channels, and reduce the rate of glutamate release from photoreceptor terminals.

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Age dependent sensitivity of the rat retina to the excitotoxic action ofN-methyl-D-aspartate

Cited by 14 publications

References 0 publications

Developmental plasticity of NMDA receptor function in the retina and the influence of light

Developmental plasticity of NMDA receptor function in the retina and the influence of light

A role for polyamines in retinal ganglion cell excitotoxic death

Zinc modulation of calcium activity at the photoreceptor terminal: A calcium imaging study

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