Activity-dependent Release of Brain-derived Neurotrophic Factor Underlies the Neuroprotective Effect of N-Methyl-d-aspartate

Marini, Ann M.; Rabin, Stuart J.; Lipsky, Robert H.; Mocchetti, Italo

doi:10.1074/jbc.273.45.29394

Cited by 193 publications

(243 citation statements)

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“…11 Brain-derived neurotrophic factor is important for appropriate development and connectivity of neurons as well as their survival. 12,13 In adults, activity dependent modulation of BDNF levels is important for synaptic plasticity and remodeling. 14,15 Activation of the extracellular-regulated kinases (ERKs) pathway by BDNF is important for neuronal survival.…”

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confidence: 99%

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

et al. 2009

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Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators include benzamide compounds that allosterically modulate AMPA glutamate receptors. These small molecules that cross the blood-brain barrier have been shown to act as a neuroprotectant by increasing the levels of endogenous brain-derived neurotrophic factor (BDNF). Positive AMPA receptor modulators have also been shown to increase the levels of growth-associated protein-43 (GAP-43). GAP-43 plays a major role in many aspects of neuronal function in vertebrates. The goal of this study was to determine whether GAP-43 was important in mediating the actions of positive AMPA receptor modulator (S18986) and BDNF. Using cortical cultures from GAP-43 knockout and control mice, we show that (1) GAP-43 is upregulated in response to S18986 and BDNF in control cultures; (2) this upregulation of GAP-43 is essential for mediating the neuroprotective effects of S18986 and BDNF; (3) administration of S18986 and BDNF leads to an increase in the expression of the glutamate transporters GLT-1 and GLAST that are key to limiting excitotoxic cell death and this increase in GLT-1 and GLAST expression is completely blocked in the absence of GAP-43. Taken together this study concludes that GAP-43 is an important mediator of the neurotrophic effects of S18986 and BDNF on neuronal survival and plasticity, and is essential for the success of positive AMPA receptor modulator-BDNF-based neurotrophin therapy. Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators allosterically modulate AMPA-type glutamate receptors and facilitate fast excitatory transmission, 1,2 and have been shown to enhance learning and memory. [3][4][5] Positive AMPA receptor modulators also decrease neuronal loss in excitotoxic neonatal brain lesions. 6 Thus, positive AMPA receptor modulators are potential candidates for treatment of diseases characterized by cognitive dysfunction and neuronal loss. 7,8 Some of the effects of positive AMPA receptor modulators are mediated via increased BDNF expression. 9,10 Positive AMPA receptor modulators however are preferred over direct administration of BDNF itself as this class of molecules readily crosses the blood-brain barrier. 11 Brain-derived neurotrophic factor is important for appropriate development and connectivity of neurons as well as their survival. 12,13 In adults, activity dependent modulation of BDNF levels is important for synaptic plasticity and remodeling. 14,15 Activation of the extracellular-regulated kinases (ERKs) pathway by BDNF is important for neuronal survival. 16,17 BDNF mediates activity dependent synaptic plasticity by mechanisms that involve receptor regulation and localized gene transcription. 18,19 At present, it is unclear whether the neuroprotection, synaptic remodeling and plasticity effects of BDNF are related to each other through common downstream elements.Growth-associated protein-43 (GAP-43) is a nervous system specific F-actin regulating phosphoprotein expressed during de...

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confidence: 99%

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

et al. 2009

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“…In cerebellar granule cells, GM1 increases the release of NT-3 (but not of BDNF) and evokes a weak induction of TrkB tyrosine phosphorylation (30), consistent with NT-3 being a weak TrkB autophosphorylation activator (37). On the other hand, LIGA20 is more potent than GM1 in activating TrkB in these neurons (30), consistent with its greater effect on BDNF release.…”

Section: Fig 6 Trkc-igg Inhibits Gm1-mediated Trkc Autophosphorylatmentioning

confidence: 55%

“…TrkB-IgG Blocks LIGA20-mediated Neuronal Protection-To further support and strengthen the release hypothesis, we tested whether TrkB-IgG, which is known to block the neuroprotective property of BDNF released in cerebellar granule cells (37), also blocks LIGA20-mediated neuroprotection. Cerebellar granule cells were exposed to TrkB-IgG (10 g/ml) immediately prior to LIGA20 (5 M); then 3 h later, a toxic concentration of glutamate (300 M) was added.…”

Section: Fig 6 Trkc-igg Inhibits Gm1-mediated Trkc Autophosphorylatmentioning

confidence: 99%

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Gangliosides Activate Trk Receptors by Inducing the Release of Neurotrophins

Rabin

Bachis

Mocchetti

2002

Journal of Biological Chemistry

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We used NIH-3T3 fibroblasts expressing the different Trk receptors to examine whether GM1 ganglioside and its semisynthetic derivative LIGA20 activate various neurotrophin receptors. GM1 induced autophosphorylation of TrkC more potently than TrkA or TrkB receptors. In contrast, LIGA20 activated TrkB tyrosine phosphorylation only. Therefore, Scatchard analysis was performed to determine whether GM1 binds to TrkC. GM1 failed to displace neurotrophin-3 binding, suggesting that this ganglioside does not act as a ligand for Trk receptors. In addition, GM1 failed to induce autophosphorylation of a chimeric receptor consisting of the extracellular domain of the tumor necrosis factor receptor and the intracellular domain of TrkA, suggesting that GM1 does not affect the tyrosine kinase domain. We next determined whether GM1 induces the release of neurotrophins from fibroblast cells. GM1 induced a rapid and significant increase in the amount of neurotrophin-3, but not other neurotrophins. This effect was independent of the presence of Trk because K252a did not prevent GM1-mediated release of neurotrophin-3. Moreover, GM1-mediated TrkC autophosphorylation was blocked by TrkC-IgG (but not TrkB-IgG) receptor bodies, further suggesting that GM1 activates TrkC by inducing the release of neurotrophin-3. This hypothesis was also tested in cultured cerebellar granule cells. GM1 induced neurotrophin-3 (but not brain-derived neurotrophic factor or nerve growth factor) release. In contrast, LIGA20 increased the secretion of brain-derived neurotrophic factor. Our data show that gangliosides may activate different Trk receptors by differentially affecting the release of neurotrophins.Gangliosides constitute a heterogeneous family of sialic acidcontaining glycosphingolipids found in relative abundance in the nervous system (1, 2), where they influence the development and/or differentiation of neurons (3-5). Interest in these molecules has grown since the discovery that gangliosides display neurotrophic properties in neurons of the central nervous system both in vitro and in vivo. Indeed, the monosialotetrahexosylganglio (GM1) 1 prevents the dramatic loss of cholinergic neurons subsequent to hippocampal ablation or cortical lesion (6 -9). GM1 also stimulates the regeneration of dopaminergic neurons (10), improves cell survival in injured substantia nigra (11), and ameliorates the abnormal motor responses in animals treated with the dopamine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (12). Moreover, GM1 and other gangliosides have been shown to possess a neuroprotective action against excitatory amino acid toxicity in vitro (13-15) and after stroke or brain ischemia (16, 17) as well as after spinal cord injury (18). Despite these findings, the mechanisms of ganglioside trophic activity are still unclear. Potential substrates of GM1 that would explain its neurotrophic effects are the neurotrophins and their receptors. The neurotrophin family of neurotrophic factors includes nerve growth factor (NGF), brain-derived neurotrophi...

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“…Preincubation of cerebellar granule cells, hippocampal neurons, or retinal explants with NMDA protects them from subsequent glutamate excitotoxicity by increasing levels of BDNF available to the cells (61)(62)(63). 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).…”

Section: Nmda Receptor-dependent Protection From Exogenous Challengementioning

confidence: 98%

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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Activity-dependent Release of Brain-derived Neurotrophic Factor Underlies the Neuroprotective Effect of N-Methyl-d-aspartate

Cited by 193 publications

References 46 publications

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

Gangliosides Activate Trk Receptors by Inducing the Release of Neurotrophins

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

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