Distinct Modes of AMPA Receptor Suppression at Developing Synapses by GluN2A and GluN2B: Single-Cell NMDA Receptor Subunit Deletion In Vivo

Gray, John A.; Shi, Yun; Usui, Hiroshi; During, Matthew J.; Sakimura, Kenji; Nicoll, Roger A.

doi:10.1016/j.neuron.2011.08.007

Cited by 264 publications

(326 citation statements)

References 90 publications

(163 reference statements)

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“…Most studies support the model in which activation of NMDARs promotes the recruitment of AMPARs to immature synapses (25,43). However, single-cell deletion of NMDARs in the hippocampus led to an up-regulation of AMPAR-EPSCs in CA1 neurons by increasing the number of functional synapses (29,44). This is in contrast with our results in the thalamus, in which deletion of NMDARs blocked the upregulation of AMPARs at the synapse.…”

Section: Discussionsupporting

confidence: 65%

“…However, such effect was not observed in another study that used single-cell deletion of GluN2B or GluN1 in the hippocampus (29). One possibility for this discrepancy is the difference in the time of deletion between these two studies, as the former used the embryonic nestin Cre driver (39), whereas the latter used viral transfection in newborn mice for Cre expression (29). However, both studies found significant reductions in spine density in hippocampal neurons without GluN2B, which is inconsistent with a role of the receptor in pruning of synapses.…”

Section: Discussionmentioning

confidence: 83%

“…In the hippocampus, neurons without GluN2B had more primary dendrites than neighboring neurons with GluN2B, presumably because of a failure in pruning supernumerary dendrites in neurons without GluN2B. However, such effect was not observed in another study that used single-cell deletion of GluN2B or GluN1 in the hippocampus (29). One possibility for this discrepancy is the difference in the time of deletion between these two studies, as the former used the embryonic nestin Cre driver (39), whereas the latter used viral transfection in newborn mice for Cre expression (29).…”

Section: Discussionmentioning

confidence: 94%

“…Consistent with this idea, chronic application of NMDAR antagonists or global knockdown of NMDARs disrupts developmental refinement of neuronal circuits in many parts of the brain (26)(27)(28). However, recent studies in the hippocampus have shown that single-cell deletion of NMDARs in newborn mice has no effect on the number or density of synaptic spines (29). These findings raised the possibility that chronic block or global knockdown of NMDARs may affect synaptic refinement through indirect mechanisms.…”

mentioning

confidence: 95%

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Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses

Zhang

Peterson

Liu

2012

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

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Neurons in the brains of newborns are usually connected with many other neurons through weak synapses. This early pattern of connectivity is refined through pruning of many immature connections and strengthening of the remaining ones. NMDA receptors (NMDARs) are essential for the development of excitatory synapses, but their role in synaptic refinement is controversial. Although chronic application of blockers or global knockdown of NMDARs disrupts developmental refinement in many parts of the brain, the ubiquitous presence of NMDARs makes it difficult to dissociate direct effects from indirect ones. We addressed this question in the thalamus by using genetic mosaic deletion of NMDARs. We demonstrate that pruning and strengthening of immature synapses are blocked in neurons without NMDARs, but occur normally in neighboring neurons with NMDARs. Our data support a model in which activation of NMDARs in postsynaptic neurons initiates synaptic refinement.D uring early development in vertebrates, neurons in many parts of the nervous system form weak synapses with a large number of target cells (1-7). This early pattern of connectivity is refined through two processes: synapse elimination that removes many initial connections and synapse maturation whereby the remaining connections are strengthened (8,9). This refinement of immature synapses is essential for the formation of neural circuits, and provides the basis for behavioral development. Many studies, in particular those conducted at the neuromuscular junction, in the cerebellum and visual pathways, have demonstrated that activity plays a central role in synaptic refinement (10-12). However, the mechanisms of synaptic refinement remain incompletely understood. At the neuromuscular junction, silencing of synaptic transmission disrupted the refinement process (13,14). The role of synaptic transmission in the refinement of central synapses seems more complex. Although manipulations of presynaptic activity disrupted the refinement of connections in the visual pathway (15-17), some of the effects were independent of synaptic transmission (18,19).The vast majority of excitatory synapses in the brain use glutamate as neurotransmitter; synaptic transmission is usually mediated by AMPA receptors (AMPARs) and NMDA receptors (NMDARs) in postsynaptic neurons. NMDARs play an important role in the development of neural circuits. In the brains of neonates, glutamatergic synapses have few or no AMPARs, and synaptic transmission is primarily mediated by NMDARs (20-23). Activation of NMDARs by correlated activity is thought to be a key mechanism underlying synaptic refinement during development (24, 25). Consistent with this idea, chronic application of NMDAR antagonists or global knockdown of NMDARs disrupts developmental refinement of neuronal circuits in many parts of the brain (26-28). However, recent studies in the hippocampus have shown that single-cell deletion of NMDARs in newborn mice has no effect on the number or density of synaptic spines (29). These findings raised the...

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 95%

See 2 more Smart Citations

Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses

Zhang

Peterson

Liu

2012

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

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“…Specifically, embryonically generated neurons face an environment with sparse synaptic activity. It was shown that under these circumstances GluN2B-containing NMDARs negatively regulate the incorporation of synaptic AMPA receptors (AMPARs) (Hall et al, 2007;Adesnik et al, 2008;Gray et al, 2011). In contrast to cortical development, adult-born neurons integrate into networks characterized by strong and concerted synaptic activity.…”

Section: Introductionmentioning

confidence: 99%

GluN2B-Containing NMDA Receptors Promote Wiring of Adult-Born Neurons into Olfactory Bulb Circuits

Kelsch

Eliava

et al. 2012

J. Neurosci.

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In the developing telencephalon, NMDA receptors (NMDARs) are composed of GluN1 and GluN2B subunits. These "young" NMDARs set a brake on synapse recruitment in neurons of the neonatal cortex. The functional role of GluN2B for synapse maturation of adult-born granule cells (GCs) in the olfactory bulb has not been established and may differ from that of differentiating neurons in immature brain circuits with sparse activity. We genetically targeted GCs by sparse retroviral delivery in mouse subventricular zone that allows functional analysis of single genetically modified cells in an otherwise intact environment. GluN2B-deficient GCs did not exhibit impairment with respect to the first developmental milestones such as synaptogenesis, dendrite formation, and maturation of inhibitory synaptic inputs. However, GluN2B deletion prevented maturation of glutamatergic synaptic input. This severe impairment in synaptic development was associated with a decreased response to novel odors and eventually led to the demise of adult-born GCs. The effect of GluN2B on GC survival is subunit specific, since it cannot be rescued by GluN2A, the subunit dominating mature NMDAR function. Our observations indicate that, GluN2B-containing NMDARs promote synapse activation in adult-born GCs that integrate in circuits with high and correlated synaptic activity. The function of GluN2B-containing NMDARs on synapse maturation can thus be bidirectional depending on the environment.

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TORC1 selectively regulates synaptic maturation and input convergence in the developing visual system

Gobert

Schohl

Kutsarova

et al. 2020

Developmental Neurobiology

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Newly synthesized proteins support the development of functional neural circuits and previous work has suggested that dysregulated translation mediates certain forms of autism spectrum disorder (ASD). Here, we investigated the role of Target of Rapamycin Complex 1 (TORC1) in synaptic and dendritic development in vivo in the retinotectal system of Xenopus laevis tadpoles. We found that TORC1 signaling regulates dendritic growth and branching and that acute over‐activation of TORC1 by Rheb overexpression drove enhanced maturation of excitatory synapses by recruiting AMPA receptors. Interestingly, TORC1 over‐activation did not affect inhibitory transmission, resulting in a significant imbalance in the excitatory‐to‐inhibitory ratio. Rheb overexpression also enlarged excitatory visual input fields in tectal neurons, consistent with dysregulation of retinotopic input refinement and integration of the cell into the circuit. In contrast to other reports that mainly found impairments in synaptic inhibition using broad systemic deletion or mutation of TORC1 regulatory proteins, our findings from acute, local manipulation of TORC1 reveal its critical role in selectively regulating the number and maturity of excitatory, but not inhibitory, synapses in the developing brain.

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Distinct Modes of AMPA Receptor Suppression at Developing Synapses by GluN2A and GluN2B: Single-Cell NMDA Receptor Subunit Deletion In Vivo

Cited by 264 publications

References 90 publications

Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses

Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses

GluN2B-Containing NMDA Receptors Promote Wiring of Adult-Born Neurons into Olfactory Bulb Circuits

TORC1 selectively regulates synaptic maturation and input convergence in the developing visual system

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