N-methyl-d-aspartate promotes the survival of cerebellar granule cells in culture

Balázs, R.; Jørgensen, Ole Steen; Hack, N.

doi:10.1016/0306-4522(88)90279-5

Cited by 455 publications

(231 citation statements)

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“…Experiments performed in vitro were the first to demonstrate that developing neurons are vulnerable to NMDA receptor hypofunc- tion and that treatment with low levels of NMDA receptor agonist can enhance neuronal survival (46)(47)(48)(49). The present conclusion that NMDA receptors protect against Bax-dependent cell death in vivo is supported by observations that moderate levels of NMDA receptor function increase Bcl-2 and decrease Bax protein levels in cultured cerebellar neurons (50).…”

Section: Mechanisms Of Nmda Receptor-regulated Neuronal Survival In Vsupporting

confidence: 51%

NMDA receptors promote survival in somatosensory relay nuclei by inhibiting Bax-dependent developmental cell death

Vaccari

Casey

Aleem

et al. 2006

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

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Naturally occurring cell death is a universal feature of developing nervous systems that plays an essential role in determining adult brain function. Yet little is known about the decisions that select a subset of CNS neurons for survival and cause others to die. We report that postnatal day 0 NMDA receptor subunit 1 (NMDAR1) knockout mice display an Ϸ2-fold increase in cell death in the brainstem trigeminal complex (BSTC), including all four nuclei that receive somatosensory inputs from the face (principalis, oralis, interpolaris, and caudalis). Treatment with the NMDA receptor antagonist dizocilpine maleate (MK-801) for 24 h before birth also caused an increase in cell death that reached statistical significance in two of the four nuclei (oralis and interpolaris). The neonatal sensitivity to NMDA receptor hypofunction in the BSTC, and in its main thalamic target, the ventrobasal nucleus (VB), coincides with the peak of naturally occurring cell death and trigeminothalamic synaptogenesis. At embryonic day 17.5, before the onset of these events, NMDAR1 knockout does not affect cell survival in either the BSTC or the VB. Immunostaining for active caspase-3 and the neuronal marker Hu specifically confirms the presence of dying neurons in the BSTC and the VB of NMDAR1 knockout neonates. Finally, genetic deletion of Bax rescues these structures from the requirement for NMDA receptors to limit naturally occurring cell death. Taken together, the results indicate that NMDA receptors play a survival role for somatosensory relay neurons during synaptogenesis by inhibiting Bax-dependent developmental cell death.brainstem ͉ neuroprotection ͉ sensory systems ͉ trophic ͉ ventrobasal N eurons in the peripheral nervous system avoid developmental cell death by successfully competing for a limiting supply of neurotrophins from synaptic target tissues (1). The situation in the developing CNS is less clear, where the survival-promoting action of neurotrophins on central neurons is complemented, facilitated, or replaced by other forms of support (2). A strong candidate for this role is the electrical activity that is present in developing neurons and neural circuits (3-5). Most neurons, including those in the somatosensory relay nuclei, express NMDA receptors before or just after exiting the cell cycle, well before synapses are established (6-10). Eliminating NMDA receptor function dramatically increases neuronal cell death during development (11-17), and NMDA receptor hypofunction has been proposed to play a causal role in fetal alcohol syndrome and schizophrenia (18,19). However, the biological significance and the molecular mechanisms of NMDA receptor-regulated neuronal survival in the intact brain remain largely unknown.NMDA receptors are best known for their role in synaptic plasticity. In the adult brain many forms of long-term potentiation and long-term depression require NMDA receptor function (20). During development, the refinement and plasticity of nascent synapses have also been shown to be dependent on NMDA receptors (2...

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Section: Mechanisms Of Nmda Receptor-regulated Neuronal Survival In Vsupporting

confidence: 51%

NMDA receptors promote survival in somatosensory relay nuclei by inhibiting Bax-dependent developmental cell death

Vaccari

Casey

Aleem

et al. 2006

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

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“…The present experiments relate specifically to neurons exposed continuously to glutamate, where the mitochondria are continuously exposed to elevated [Ca 2+ ] c , in contrast to the delayed cell death induced by transient glutamate exposure. Although low KCl media initiate apoptosis in this preparation (Gallo et al 1987;Peng et al 1991) this is prevented by NMDA receptor activation (Balázs et al 1988;Bhave et al 1999) and thus is not a factor in the present experimental design. This is important, as there is ample evidence that apoptotic neuronal cell death is ameliorated by antioxidants (Patel 1998;Iacovitti et al 1999;González-Polo et al 2003).…”

Section: Discussionmentioning

confidence: 97%

Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate

Vesce

Kirk

Nicholls

2004

Journal of Neurochemistry

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The relationship is investigated between superoxide levels in single cultured rat cerebellar granule neurons exposed continuously to glutamate in low KCl medium and the deregulation of cytoplasmic Ca 2+ . Cells that maintain a regulated cytoplasmic-free Ca 2+ and mitochondrial polarization in the presence of glutamate show no increase in superoxide levels until the onset of cytoplasmic Ca 2+ deregulation. Oxidative stress of mitochondrial origin is readily detectable, as the inhibitors rotenone and antimycin A markedly increase superoxide levels with no effect on cytoplasmic-free Ca 2+ . The potent cell-permeant superoxide dismutase/catalase mimetic manganese tetrakis (N-ethylpyridinium-2yl) porphyrin, MnTE-PyP, abolishes the deregulation-related increase in superoxide but has no effect on deregulation itself. A combination of catalase with the free radical scavenger 4-hydroxy-TEMPO also fails to reduce deregulation. Following the loss of Ca 2+ homeostasis nuclei undergo condensation; this morphological change is not inhibited by MnTE-PyP and cannot account for the increased ethidium fluorescence. Phospholipase A 2 inhibitors decrease the deregulation-related increase in superoxide without protecting against deregulation. In conclusion, our study indicates that deregulation is not caused by NMDA receptor-mediated oxidative stress as NMDA receptor activation does not increase superoxide levels until the onset of deregulation. Furthermore, the majority of superoxide is produced in the cytoplasm rather than in mitochondria.

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“…NMDA receptor stimulation can protect against cell death resulting from both the withdrawal of trophic factors and excitotoxic insults (Balazs et al, 1988;Chuang et al, 1992;Rocha et al, 1999;Raval et al, 2003). NMDA receptor-mediated neuroprotection is a transcriptionally dependent process (Marini and Paul, 1992) that appears to be dependent, in part, on the expression of both the anti-apoptotic gene BCL-2 (Mabuchi et al, 2001;Alavez et al, 2003) and the neurotrophin BDNF (Aliaga et al, 1998;Rocha et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Activity-Dependent Neuroprotection and cAMP Response Element-Binding Protein (CREB): Kinase Coupling, Stimulus Intensity, and Temporal Regulation of CREB Phosphorylation at Serine 133

et al. 2005

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The dual nature of the NMDA receptor as a mediator of excitotoxic cell death and activity-dependent cell survival likely results from divergent patterns of kinase activation, transcription factor activation, and gene expression. To begin to address this divergence, we examined cellular and molecular signaling events that couple excitotoxic and nontoxic levels of NMDA receptor stimulation to activation of the cAMP response element-binding protein (CREB)/cAMP response element (CRE) pathway in cultured cortical neurons. Pulses (10 min) of NMDA receptor-mediated synaptic activity (nontoxic) triggered sustained (up to 3 h) CREB phosphorylation (pCREB) at serine 133. In contrast, brief stimulation with an excitotoxic concentration of NMDA (50 M) triggered transient pCREB. The duration of pCREB was dependent on calcineurin activity. Excitotoxic levels of NMDA stimulated calcineurin activity, whereas synaptic activity did not. Calcineurin inhibition reduced NMDA toxicity and converted the transient increase in pCREB into a sustained increase. In accordance with these observations, sustained pCREB (up to 3 h) did not require persistent kinase pathway activity. The sequence of stimulation with excitotoxic levels of NMDA and neuroprotective synaptic activity determined which stimulus exerted control over pCREB duration. Constitutively active and dominant-negative CREB constructs were used to implicate CREB in synaptic activity-dependent neuroprotection against NMDA-induced excitotoxicity. Together these data provide a framework to begin to understand how the neuroprotective and excitotoxic effects of NMDA receptor activity function in an antagonistic manner at the level of the CREB/CRE transcriptional pathway.

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N-methyl-d-aspartate promotes the survival of cerebellar granule cells in culture

Cited by 455 publications

References 48 publications

NMDA receptors promote survival in somatosensory relay nuclei by inhibiting Bax-dependent developmental cell death

NMDA receptors promote survival in somatosensory relay nuclei by inhibiting Bax-dependent developmental cell death

Relationships between superoxide levels and delayed calcium deregulation in cultured cerebellar granule cells exposed continuously to glutamate

Activity-Dependent Neuroprotection and cAMP Response Element-Binding Protein (CREB): Kinase Coupling, Stimulus Intensity, and Temporal Regulation of CREB Phosphorylation at Serine 133

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