Obligatory Role of NR2A for Metaplasticity in Visual Cortex

Philpot, Benjamin D.; Cho, Kathleen K.A.; Bear, Mark F.

doi:10.1016/j.neuron.2007.01.027

Cited by 168 publications

(184 citation statements)

References 61 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…Given the lack of an effective pharmacological tool to explore the role of the NR2A subunit (see Berberich et al, 2005;Weitlauf et al, 2005;Frizelle et al, 2006;Neyton and Paoletti, 2006;Kash and Winder, 2007), we utilized NR2A KO mice to determine the functional synaptic presence of the NR2A subunit in the vBNST. While NMDA-EPSCs were still readily elicited in vBNST neurons from NR2A KO mice, there was a significant alteration in the kinetics of the response ( Figures 3a-c), consistent with what has been demonstrated in other brain regions (Fu et al, 2005;Lu et al, 2006;Philpot et al, 2007). Both the decay time (294747 ms for the NR2A KO, n ¼ 12; 128720 ms for the wild type, n ¼ 10; po0.01; Figure 3b) and the rise time (1171 ms for the NR2A KO, n ¼ 12; 6.670.3 ms for the wild type, n ¼ 10; po0.01; Figure 3c) were significantly slower when compared to wild-type animals.…”

Section: Nr2a and Nr2b Subunits Contribute To Synaptic Nmdars In The supporting

confidence: 87%

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Kash

Matthews

Winder

2007

Neuropsychopharmacol

View full text Add to dashboard Cite

Components of the mesolimbic dopamine system, in particular dopaminergic cells in the ventral tegmental area (VTA), have been implicated in the acute reinforcing actions of ethanol. The ventral bed nucleus of the stria terminalis (vBNST) potently regulates dopaminergic cell firing in the VTA, and has been implicated in the behavioral actions of ethanol. The N-methyl-D-asparate receptor (NMDAR) is a major molecular target of ethanol, however, current evidence suggests that ethanol regulation of NMDAR function is widely variable and likely depends on a number of factors. Thus, it is critical to investigate ethanol regulation of NMDAR function at synapses relevant to ethanol-regulated behaviors, such as in the vBNST. Here we show, using multiple techniques, that ethanol inhibits NMDAR function in vBNST neurons in a postsynaptic fashion. Further, we demonstrate the functional presence of both NR2A and NR2B-containing NMDARs in the vBNST. While genetic removal of NR2A did not alter the magnitude of ethanol inhibition, pharmacological blockade of NR2B rendered synaptically activated NMDARs insensitive to ethanol inhibition. Finally, we demonstrate that ethanol inhibits NMDARs in cells in the vBNST that project to the VTA, providing a direct means by which ethanol in the vBNST can modulate the dopaminergic system.

show abstract

Section: Nr2a and Nr2b Subunits Contribute To Synaptic Nmdars In The supporting

confidence: 87%

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Kash

Matthews

Winder

2007

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…The coincident alterations in the NR2A/NR2B ratio and in the LTP/LTD inspired the assumption that changes in NR2A/NR2B lead to sliding of LTP/LTD (Bear, 1995;Quinlan et al, 1999a,b;Philpot et al, 2007;Yashiro and Philpot, 2008). They put forward a hypothesis that activitydependent changes in NR2A/NR2B are involved in metaplastic regulation of the LTP/LTD threshold (Morishita et al, 2007;Yashiro and Philpot, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…A series of elegant investigations by Bear's laboratory in layer 3 of the visual cortex demonstrated that the "sliding threshold" is an attractive mechanism based on experience-dependent alterations in NMDARs (Kirkwood et al, 1996;Quinlan et al, 1999a,b;Philpot et al, 2001Philpot et al, , 2003Philpot et al, , 2007Shouval et al, 2002;Bear, 2003;Iny et al, 2006). The coincident alterations in the NR2A/NR2B ratio and in the LTP/LTD inspired the assumption that changes in NR2A/NR2B lead to sliding of LTP/LTD (Bear, 1995;Quinlan et al, 1999a,b;Philpot et al, 2007;Yashiro and Philpot, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…They put forward a hypothesis that activitydependent changes in NR2A/NR2B are involved in metaplastic regulation of the LTP/LTD threshold (Morishita et al, 2007;Yashiro and Philpot, 2008). Although a recent study using genetic ablation of NR2A suggests an obligatory role of NR2A for metaplasticity in the visual cortex, and thus adds new support to this hypothesis (Philpot et al, 2007), there is no direct examination whether and how activity-dependent changes in the NR2A/NR2B ratio take an active role in bidirectional metaplastic regulation of the LTP/LTD threshold. Resolving this question will be very helpful to understand in depth the role of NR2 subunits in the regulation of synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metaplastic Regulation of Long-Term Potentiation/Long-Term Depression Threshold by Activity-Dependent Changes of NR2A/NR2B Ratio

Chen²,

Gu³

et al. 2009

Journal of Neuroscience

View full text Add to dashboard Cite

In vivo experience induces changes in synaptic NMDA receptor (NMDAR) subunit components, which are correlated with subsequent modifications of synaptic plasticity. However, little is known about how these subunit changes regulate the induction threshold of subsequent plasticity. At hippocampal Schaffer collateral-CA1 synapses, we first examined whether a recent history of neuronal activity could affect subsequent synaptic plasticity through its actions on NMDAR subunit components. We found that prior activity history produced by priming stimulations (PSs) across a wide range of frequencies (1-100 Hz) could induce bidirectional changes in the NR2A/NR2B ratio, which governs the threshold for subsequent long-term potentiation/long-term depression (LTP/LTD). Manipulating the NR2A/NR2B ratio through partial NR2 subunit blockade mimicked the PS regulation of the LTP/LTD threshold. Our results demonstrate that activity-dependent changes in the NR2A/NR2B ratio can be critical factors in metaplastic regulation of the LTP/LTD threshold.

show abstract

“…It is now understood that the qualities of cortical synaptic plasticity depend on the recent history of cortical activity, a property called metaplasticity (23). After a period of attenuated cortical activity, the threshold for synaptic potentiation is reduced (24)(25)(26). Thus, the period of quiescence that immediately follows initiation of reverse occlusion lowers the threshold for synaptic potentiation, enabling subsequent visual experience to increase synaptic effectiveness when it would have otherwise been without effect (27).…”

mentioning

confidence: 99%

Rapid recovery from the effects of early monocular deprivation is enabled by temporary inactivation of the retinas

Fong

Mitchell

Duffy

et al. 2016

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

Self Cite

View full text Add to dashboard Cite

A half-century of research on the consequences of monocular deprivation (MD) in animals has revealed a great deal about the pathophysiology of amblyopia. MD initiates synaptic changes in the visual cortex that reduce acuity and binocular vision by causing neurons to lose responsiveness to the deprived eye. However, much less is known about how deprivation-induced synaptic modifications can be reversed to restore normal visual function. One theoretically motivated hypothesis is that a period of inactivity can reduce the threshold for synaptic potentiation such that subsequent visual experience promotes synaptic strengthening and increased responsiveness in the visual cortex. Here we have reduced this idea to practice in two species. In young mice, we show that the otherwise stable loss of cortical responsiveness caused by MD is reversed when binocular visual experience follows temporary anesthetic inactivation of the retinas. In 3-mo-old kittens, we show that a severe impairment of visual acuity is also fully reversed by binocular experience following treatment and, further, that prolonged retinal inactivation alone can erase anatomical consequences of MD. We conclude that temporary retinal inactivation represents a highly efficacious means to promote recovery of function. A mblyopia is a widespread form of human visual disability that arises from imbalanced visual experience in the two eyes during infancy or early childhood. The core pathophysiological process underlying amblyopia is ocular dominance plasticity in the primary visual cortex (V1). Ocular dominance plasticity, evolutionarily conserved in mammals with binocular vision, has become a classic paradigm for studying how brain development is influenced by experience and deprivation. A brief period of monocular deprivation (MD) during early postnatal life causes functional depression of synapses in V1 that serve the deprived eye (1-7). Consequently, early-life MD severely and persistently degrades visual acuity through the deprived eye, which typically fails to recover spontaneously when binocular vision is restored (8-10). A critical step in developing targeted interventions for treating amblyopia is to identify strategies for reversing deprivation-driven synaptic modifications in V1.The traditional approach to promote recovery following MD has been to occlude the strong eye to force vision through the weak amblyopic eye. This "reverse occlusion" approach has been validated in animals (11, 12) and represents the cornerstone of current treatment (patching therapy) of human amblyopia (13-16). However, this treatment has well-known limitations that include poor compliance, potential loss of vision through the newly patched eye, failure to recover binocular vision, and a declining treatment efficacy with age (15, 17-21). Nevertheless, the success of reverse occlusion strategies demonstrates that severely weakened synaptic inputs in the brain can be rejuvenated under appropriate circumstances.An insight into how reverse occlusion might promote recovery came fr...

show abstract

Obligatory Role of NR2A for Metaplasticity in Visual Cortex

Cited by 168 publications

References 61 publications

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Metaplastic Regulation of Long-Term Potentiation/Long-Term Depression Threshold by Activity-Dependent Changes of NR2A/NR2B Ratio

Rapid recovery from the effects of early monocular deprivation is enabled by temporary inactivation of the retinas

Contact Info

Product

Resources

About