Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain

Hansen, Henrik H.; Briem, Tim Benjamin; Dzietko, Mark; Sifringer, Marco; Voß, Alexander; Rzeski, Wojciech; Zdzisińska, Barbara; Thor, Friederike; Heumann, Rolf; Stepulak, Andrzej; Bittigau, Petra; Ikonomidou, Chrysanthy

doi:10.1016/j.nbd.2004.03.013

Cited by 154 publications

(157 citation statements)

References 51 publications

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“…It has been proposed that normal endogenous NMDA receptor function acts as a survival signal for developing neurons. Consistent with this idea, blocking NMDA receptors suppresses Bcl-2 and induces Bax in the forebrain of developing rats (17,43). The present finding that NMDA receptors, like classic survival factors (e.g., NGF) (44), protect neurons from Bax-dependent developmental cell death provides strong new support for the hypothesis that moderate NMDA receptor activity acts as a survival signal for developing neurons in vivo.…”

Section: Nmda Receptor Function As a Survival Signal For Developing Nmentioning

confidence: 83%

“…This suggests that BDNF may also facilitate NMDA-dependent attenuation of developmental cell death, a possibility that is supported by the BDNF-mediated protective role of NMDA receptors on developing retinal explants (64,65). Finally, MK-801 administration during development in vivo induces cell death and decreases both BDNF and active ERK1͞2 in the retrosplenial and cingulate cortices, further implicating these molecules in NMDA receptordependent protection of developing neurons (17).…”

Section: Nmda Receptor-dependent Protection From Exogenous Challengementioning

confidence: 89%

“…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)(7)(8)(9)(10). Eliminating NMDA receptor function dramatically increases neuronal cell death during development (11)(12)(13)(14)(15)(16)(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.…”

mentioning

confidence: 99%

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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: Nmda Receptor Function As a Survival Signal For Developing Nmentioning

confidence: 83%

Section: Nmda Receptor-dependent Protection From Exogenous Challengementioning

confidence: 89%

mentioning

confidence: 99%

See 1 more Smart Citation

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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“…Pre-clinical data comes from neonatal head-injured rats, in which apoptotic cell death contributes to neuronal injury in an age-dependent fashion and is the predominant mechanism of cell death in the most vulnerable ages [54]. The period of enhanced vulnerability coincides with a time of synaptogenesis and rapid brain growth -a comparable period in humans begins prenatally, which continues for several years after birth [55].…”

Section: How Is Tbi Different In Children?mentioning

confidence: 99%

“…Exposure to drugs that inhibit N-Methyl-D-aspartate-type glutamate receptors or that activate gamma-aminobutyric acid receptors has been shown to lead to widespread and dose-dependent neurological cell death and long-lasting neurocognitive deficits in developing animal models [157]. Neurotoxicity may be enhanced during certain critical periods of brain development [55]. Evidence has suggested that even brief exposures to anti-excitatory, neurotransmitter-blocking medications might cause increased apoptotic cell death and cognitive impairment in animals.…”

Section: Neuromonitoring and Neuroprotection In The Picumentioning

confidence: 99%

Pediatric Neurocritical Care

Murphy

2012

Neurotherapeutics

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Pediatric neurocritical care is an emerging multidisciplinary field of medicine and a new frontier in pediatric critical care and pediatric neurology. Central to pediatric neurocritical care is the goal of improving outcomes in critically ill pediatric patients with neurological illness or injury and limiting secondary brain injury through optimal critical care delivery and the support of brain function. There is a pressing need for evidence based guidelines in pediatric neurocritical care, notably in pediatric traumatic brain injury and pediatric stroke. These diseases have distinct clinical and pathophysiological features that distinguish them from their adult counterparts and prevent the direct translation of the adult experience to pediatric patients. Increased attention is also being paid to the broader application of neuromonitoring and neuroprotective strategies in the pediatric intensive care unit, in both primary neurological and primary non-neurological disease states. Although much can be learned from the adult experience, there are important differences in the critically ill pediatric population and in the circumstances that surround the emergence of neurocritical care in pediatrics.

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Mechanisms and Consequences of Anesthetic‐Induced Neuroapoptosis in the Developing Brain

Zhou

Januszewski

Maze

et al. 2012

Anesthesia and the Fetus

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Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain

Cited by 154 publications

References 51 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

Pediatric Neurocritical Care

Mechanisms and Consequences of Anesthetic‐Induced Neuroapoptosis in the Developing Brain

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