Functional NMDA Receptors at Axonal Growth Cones of Young Hippocampal Neurons

Wang, Philip Y.; Petralia, Ronald S.; Wang, Yaxian; Wenthold, Robert J.; Brenowitz, Stephan D.

doi:10.1523/jneurosci.5639-10.2011

Cited by 38 publications

(41 citation statements)

References 58 publications

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“…The presence of NR1 in association with synaptic vesicles suggests that, in analogy to presynaptic AMPARs, NMDARs can be dynamically internalized by endocytosis and exposed to the presynaptic membrane by exocytosis in response to electrical activity and activation of signal transduction cascades. In addition, the localization of presynaptic NMDARs is developmentally regulated given that NMDARs are not found in synaptic vesicles in mature neurons in vivo, consistent with previous studies of presynaptic NMDAR function in cortical slices (Corlew et al, 2007;Wang et al, 2011).…”

Section: Presynaptic Nmdarssupporting

confidence: 87%

“…Consistent with the latter hypothesis, growth cone behavior is strongly regulated by neurotransmitters and intracellular Ca 2+ (Gomez and Spitzer, 2000;Henley et al, 2004;Ruediger and Bolz, 2007;van Kesteren and Spencer, 2003). In addition to functional NMDARs (Wang et al, 2011), growth cones also express functional AMPARs that are internalized or exposed to the surface upon activity (Schenk et al, 2003). In excitatory neurons, vesicles within axonal growth cones and their filopodia are thought to be capable of glutamate release (Sabo and McAllister, 2003), raising the intriguing possibility that both NMDA and AMPA receptors in growth cones might act as autoreceptors.…”

Section: Dynamic Nmdars In Axonal Growth Conesmentioning

confidence: 83%

“…Dynamic NMDARs are present within structures that are involved in axonal synaptogenesis NMDARs are present in axonal growth cones of immature hippocampal neurons (Ehlers et al, 1998;Herkert et al, 1998;Wang et al, 2011), but their dynamics within growth cones have not yet been reported. Consistent with these reports, we observed bright NR1-GFP puncta in axonal growth cones of developing cortical neurons.…”

Section: Nmdars Are Transported Along Developing Axons Independently mentioning

confidence: 99%

“…Furthermore, axonal NMDAR expression is highest during the postnatal first two weeks, a period of intense synapse formation, but is dramatically decreased later in development (Corlew et al, 2007;Ehlers et al, 1998;Herkert et al, 1998;Song et al, 2009;Wang et al, 2011). Therefore, it has been hypothesized that presynaptic NMDARs might facilitate synapse formation (Corlew et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Presynaptic NMDA receptors: dynamics and distribution in developing axons in vitro and in vivo

Gill

Droubi

Giovedì

et al. 2014

Journal of Cell Science

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BSTRACTDuring cortical development, N-methyl-D-aspartate (NMDA) receptors (NMDARs) facilitate presynaptic terminal formation, enhance neurotransmitter release and are required in presynaptic neurons for spike-timing-dependent long-term depression (tLTD). However, the extent to which NMDARs are found within cortical presynaptic terminals has remained controversial, and the subsynaptic localization and dynamics of axonal NMDARs are unknown. Here, using live confocal imaging and biochemical purification of presynaptic membranes, we provide strong evidence that NMDARs localize to presynaptic terminals in vitro and in vivo in a developmentally regulated manner. The NR1 and NR2B subunits (also known as GRIN1 and GRIN2B, respectively) were found within the active zone membrane, where they could respond to synaptic glutamate release. Surprisingly, NR1 also appeared in glutamatergic and GABAergic synaptic vesicles. During synaptogenesis, NR1 was mobile throughout axons -including growth cones and filopodia, structures that are involved in synaptogenesis. Upon synaptogenic contact, NMDA receptors were quickly recruited to terminals by neuroligin-1 signaling. Unlike dendrites, the trafficking and distribution of axonal NR1 were insensitive to activity changes, including NMDA exposure, local glutamate uncaging or action potential blockade. These results support the idea that presynaptic NMDARs play an early role in presynaptic development.

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Section: Presynaptic Nmdarssupporting

confidence: 87%

Section: Dynamic Nmdars In Axonal Growth Conesmentioning

confidence: 83%

Section: Nmdars Are Transported Along Developing Axons Independently mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Presynaptic NMDA receptors: dynamics and distribution in developing axons in vitro and in vivo

Gill

Droubi

Giovedì

et al. 2014

Journal of Cell Science

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“…It is thus unlikely that our finding that AMPA but not NMDA receptors mediate glutamate-induced enhancements of protein synthesis in axons is due to the absence of NMDA receptors from these axons. Furthermore, previous studies have indicated that both AMPA and NMDA receptors are present in the axons of young neurons (55)(56)(57)(58) and that NMDA receptors are absent from the axons of older neurons (55,56,58). Our finding of the presence of AMPA and NMDA receptors in axons emitting from older neurons, at DIV 16, may be related to the fact that these axons do not form synapses in the region 2 area, whereas axons in conventional cultures actively participate in synaptogenesis after the 1st week in vitro (59).…”

Section: Glutamate-enhanced Protein Synthesis In Cortical Axonsmentioning

confidence: 99%

Glutamate Stimulates Local Protein Synthesis in the Axons of Rat Cortical Neurons by Activating α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors and Metabotropic Glutamate Receptors

Hsu

Chung

et al. 2015

Journal of Biological Chemistry

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Background: Transient rise of extracellular glutamate occurs in the developing brain. Results: Glutamate stimulates axonal translation by binding to AMPA receptors and metabotropic glutamate receptors and activating Ca 2ϩ and mTOR signaling. Conclusion: Exposure to glutamate rapidly up-regulates local translation in migrating axons. Significance: Glutamate-induced stimulation of local translation partakes in regulating axonal functions during development.

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Overstimulation of Glutamate Signals Leads to Hippocampal Transcriptional Plasticity in Hamsters

et al. 2014

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It's known that neurons in mammalian hibernators are more tolerant to hypoxia than those in non-hibernating species and as a consequence animals are capable of awakening from the arousal state without exhibiting cerebral damages. In addition, evidences have suggested that euthermic hamster neurons display protective adaptations against hypoxia, while those of rats are not capable, even though molecular mechanisms involved in similar neuroprotective strategies have not been yet fully studied. In the present work, overstimulation of glutamatergic receptors NMDA recognized as one of the major death-promoting element in hypoxia, accounted for altered network complexity consistent with a moderate reduction of hippocampal neuronal survival (p < 0.05) in hamsters. These alterations appeared to be featured concomitantly with altered glutamatergic signaling as indicated by significant down-regulation (p < 0.01) of NMDAergic (NR2A) and AMPAergic (GluR1, R2) receptor subtypes together with the metabotropic mGluR5 subtype. Diminished mRNA levels were also reported for NMDA receptor binding factors and namely PSD95 plus DREAM, which exert positive and negative regulatory properties, respectively, on receptor trafficking events. Conversely, involvement of glutamatergic signaling systems on neuronal excitotoxicity was strengthened by the co-activation of GABAAR-mediated effects as indicated by toxic morphological effects being notably reduced along with up-regulated GluR1, GluR2, mGluR5, DREAM, and Homer1c scaffold proteins when muscimol was added. Overall, these results point to a neuroprotective role of the GABAergic system against excitotoxicity episodes via DREAM-dependent inhibition of NMDA receptor and activation of AMPA receptor plus mGluR5, respectively, thus proposing them as novel therapeutic targets against cerebral ischemic damages in humans.

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Functional NMDA Receptors at Axonal Growth Cones of Young Hippocampal Neurons

Cited by 38 publications

References 58 publications

Presynaptic NMDA receptors: dynamics and distribution in developing axons in vitro and in vivo

Presynaptic NMDA receptors: dynamics and distribution in developing axons in vitro and in vivo

Glutamate Stimulates Local Protein Synthesis in the Axons of Rat Cortical Neurons by Activating α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors and Metabotropic Glutamate Receptors

Overstimulation of Glutamate Signals Leads to Hippocampal Transcriptional Plasticity in Hamsters

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