Elimination of Redundant Synaptic Inputs in the Absence of Synaptic Strengthening

Wang, Hao; Liu, Hong; Zhang, Zhong-wei

doi:10.1523/jneurosci.4569-11.2011

Cited by 18 publications

(32 citation statements)

References 38 publications

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“…Excitatory synaptic currents (EPSCs) were evoked at VPm relay synapses by stimulation applied to the medial lemniscus. The VPm relay synapse has few GluA2-containing AMPARs (30); EPSCs recorded at +40 mV are dominated by slow NMDAR-mediated currents (i.e., NMDAR-EPSCs), whereas the fast EPSCs at −70 mV are mediated by AMPARs (i.e., AMPAR-EPSCs). VPm neurons were chosen randomly for recording.…”

Section: Resultsmentioning

confidence: 99%

“…As in many other brain areas, the maturation of vibrissal relay synapses is marked by a rapid increase in the amplitude of AMPAR-EPSCs (5,30,32). To determine the role of NMDARs in synaptic maturation, we analyzed AMPAR-EPSCs in SERT-Grin1 −/− mice.…”

Section: Resultsmentioning

confidence: 99%

“…One possibility for this discrepancy is the differences in AMPAR composition between these two synapses. The Schaffer collateral-CA1 synapse contains receptors made of mostly GluA1 and GluA2 subunits (45), whereas the vibrissal relay synapse in the thalamus expresses receptors made of mostly GluA3 and GluA4 subunits (30). As the trafficking of AMPARs is regulated through subunit-specific mechanisms (46,47), a difference in subunit composition could result in different responses to NMDAR deletion.…”

Section: Discussionmentioning

confidence: 99%

“…VPm relay synapses undergo extensive refinement during the second week after birth (5). At postnatal day (P) 7, each VPm neuron is contacted by approximately six ascending axons from the brainstem; by P14, the majority of neurons receive a single ascending axon (30). The pruning of redundant inputs was accompanied by strengthening of remaining inputs.…”

mentioning

confidence: 99%

“…The pruning of redundant inputs was accompanied by strengthening of remaining inputs. At P7, transmission at VPm relay synapses is mediated primarily by NMDARs; the number of AMPARs increases rapidly during the second week (30). To selectively examine the role of NMDARs in postsynaptic neurons, we performed mosaic deletion of NMDARs in the VPm of newborn mice.…”

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confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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Developmental Impairments of Synaptic Refinement in the Thalamus of a Mouse Model of Fragile X Syndrome

Wu,

Liu,

Wang

et al. 2023

Neurosci. Bull.

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While somatosensory over-reactivity is a common feature of autism spectrum disorders such as fragile X syndrome (FXS), the thalamic mechanisms underlying this remain unclear. Here, we found that the developmental elimination of synapses formed between the principal nucleus of V (PrV) and the ventral posterior medial nucleus (VPm) of the somatosensory system was delayed in fragile X mental retardation 1 gene knockout (Fmr1 KO) mice, while the developmental strengthening of these synapses was disrupted. Immunohistochemistry showed excessive VGluT2 puncta in mutants at P12–13, but not at P7–8 or P15–16, confirming a delay in somatic pruning of PrV-VPm synapses. Impaired synaptic function was associated with a reduction in the frequency of quantal AMPA events, as well as developmental deficits in presynaptic vesicle size and density. Our results uncovered the developmental impairment of thalamic relay synapses in Fmr1 KO mice and suggest that a thalamic contribution to the somatosensory over-reactivity in FXS should be considered.

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Monogenic models of absence epilepsy

Maheshwari

Noebels

2014

Progress in Brain Research

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Elimination of Redundant Synaptic Inputs in the Absence of Synaptic Strengthening

Cited by 18 publications

References 38 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

Developmental Impairments of Synaptic Refinement in the Thalamus of a Mouse Model of Fragile X Syndrome

Monogenic models of absence epilepsy

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