Development of NMDA NR2 subunits and their roles in critical period maturation of neocortical GABAergic interneurons

Zhi, Zhang; Sun, Qian‐Quan

doi:10.1002/dneu.20844

Cited by 52 publications

(39 citation statements)

References 162 publications

(239 reference statements)

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“…These results suggest that while the cells are still alive, their developmental maturation may be affected. Similar results were recently obtained using a mouse line expressing GFP in all GABAergic neurons (252). In this study, using an NR2A-preferring antagonist, the authors showed that prolonged blockade of NR2A-containing receptors in vivo during the critical period of plasticity in the barrel cortex produced a decrease in PV expression and an alteration of fast-spiking-mediated inhibitory postsynaptic currents onto principal neurons.…”

Section: Nox2 In Schizophreniasupporting

confidence: 71%

“…PV + neurons in the rodent PFC express high levels of functional NMDARs during the first 3-4 postnatal weeks, and the activity of these receptors is necessary for the normal development of their characteristic fast-spiking (107,236,246,252). Interestingly, NMDARs in these neurons have a different subunit composition than that found in neighboring pyramidal neurons, with NR2A/NR2B ratios of 5:1 in PV + neurons and 1:1 in pyramidal neurons (107,246).…”

Section: Nmdars In Inhibitory Neuronsmentioning

confidence: 96%

“…weeks of development (51, 71,175,236,252). Oxidative modification of neurotransmitter transporters (such as glutamate transporters) and ligand-gated ion-channels (such as GABA A and NMDARs) and consequent decrease of their activity might be another target by which oxidative stress alters the development of PV + neurons.…”

Section: Nox2 In Schizophreniamentioning

confidence: 99%

“…Glutamatergic neurotransmission preferentially activates Ca 2 + -permeable AMPA receptors on mature PV + interneurons, and these receptors appear slowly during postnatal development (72,237). The expression and function of NMDARs in PV + neurons change during postnatal development, with high levels being expressed early during postnatal development and profound functional changes occurring during adolescence (21,107,236,252).…”

Section: Nox2 In Schizophreniamentioning

confidence: 99%

See 3 more Smart Citations

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

Wang

Pinto-Duarte

Sejnowski

et al. 2013

Antioxidants & Redox Signaling

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Significance: Schizophrenia is a complex neuropsychiatric disorder affecting around 1% of the population worldwide. Its mode of inheritance suggests a multigenic neurodevelopmental disorder with symptoms appearing during late adolescence/early adulthood, with its onset strongly influenced by environmental stimuli. Many neurotransmitter systems, including dopamine, glutamate, and gamma-aminobutyric acid, show alterations in affected individuals, and the behavioral and physiological characteristics of the disease can be mimicked by drugs that produce blockade of N-methyl-d-aspartate glutamate receptors (NMDARs). Recent Advances: Mounting evidence suggests that drugs that block NMDARs specifically impair the inhibitory capacity of parvalbumin-expressing (PV+) fast-spiking neurons in adult and developing rodents, and alterations in these inhibitory neurons is one of the most consistent findings in the schizophrenic postmortem brain. Disruption of the inhibitory capacity of PV+ inhibitory neurons will alter the functional balance between excitation and inhibition in prefrontal cortical circuits producing impairment of working memory processes such as those observed in schizophrenia. Critical Issues: Mechanistically, the effect of NMDAR antagonists can be attributed to the activation of the Nox2-dependent reduced form of nicotinamide adenine dinucleotide phosphate oxidase pathway in cortical neurons, which is consistent with the emerging role of oxidative stress in the pathogenesis of mental disorders, specifically schizophrenia. Here we review the mechanisms by which NMDAR antagonists produce lasting impairment of the cortical PV+ neuronal system and the roles played by Nox2-dependent oxidative stress mechanisms. Future Directions: The discovery of the pathways by which oxidative stress leads to unbalanced excitation and inhibition in cortical neural circuits opens a new perspective toward understanding the biological underpinnings of schizophrenia.

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Section: Nox2 In Schizophreniasupporting

confidence: 71%

Section: Nmdars In Inhibitory Neuronsmentioning

confidence: 96%

Section: Nox2 In Schizophreniamentioning

confidence: 99%

Section: Nox2 In Schizophreniamentioning

confidence: 99%

See 2 more Smart Citations

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

Wang

Pinto-Duarte

Sejnowski

et al. 2013

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…The role of NMDARs in developing interneurons has remained elusive. Interneurons express NMDARs, and synaptic NMDARmediated excitatory postsynaptic currents increase robustly between P6 and P8-10 (Zhang and Sun, 2011). Later, interneurons downregulate NMDAR currents (Wang and Gao, 2010), which could explain why NMDARs play no role in the recruitment of feed-forward inhibition by adult thalamocortical inputs (Hull et al, 2009;Ling and Benardo, 1995).…”

Section: Nmdars and Vgccs Mediate Dendritic Growth Triggered By Selecmentioning

confidence: 99%

Cell class-specific regulation of neocortical dendrite and spine growth by AMPA receptor splice and editing variants

et al. 2011

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SUMMARYGlutamatergic transmission converging on calcium signaling plays a key role in dendritic differentiation. In early development, AMPA receptor (AMPAR) transcripts are extensively spliced and edited to generate subunits that differ in their biophysical properties. Whether these subunits have specific roles in the context of structural differentiation is unclear. We have investigated the role of nine GluA variants and revealed a correlation between the expression of flip variants and the period of major dendritic growth. In interneurons, only GluA1(Q)-flip increased dendritic length and branching. In pyramidal cells, GluA2(Q)-flop, GluA2(Q)-flip, GluA3(Q)-flip and calcium-impermeable GluA2(R)-flip promoted dendritic growth, suggesting that flip variants with slower desensitization kinetics are more important than receptors with elevated calcium permeability. Imaging revealed significantly higher calcium signals in pyramidal cells transfected with GluA2(R)-flip as compared with GluA2(R)-flop, suggesting a contribution of voltage-activated calcium channels. Indeed, dendritic growth induced by GluA2(R)-flip in pyramidal cells was prevented by blocking NMDA receptors (NMDARs) or voltage-gated calcium channels (VGCCs), suggesting that they act downstream of AMPARs. Intriguingly, the action of GluA1(Q)-flip in interneurons was also dependent on NMDARs and VGCCs. Cell class-specific effects were not observed for spine formation, as GluA2(Q)-flip and GluA2(Q)-flop increased spine density in pyramidal cells as well as in interneurons. The results suggest that AMPAR variants expressed early in development are important determinants for activity-dependent dendritic growth in a cell type-specific and cell compartment-specific manner.

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Ionotropic glutamate receptors: Which ones, when, and where in the mammalian neocortex

Hadžić

Jack

Wahle

2016

J of Comparative Neurology

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A multitude of 18 iGluR receptor subunits, many of which are diversified by splicing and RNA editing, localize to >20 excitatory and inhibitory neocortical neuron types defined by physiology, morphology, and transcriptome in addition to various types of glial, endothelial, and blood cells. Here we have compiled the published expression of iGluR subunits in the areas and cell types of developing and adult cortex of rat, mouse, carnivore, bovine, monkey, and human as determined with antibody- and mRNA-based techniques. iGluRs are differentially expressed in the cortical areas and in the species, and all have a unique developmental pattern. Differences are quantitative rather than a mere absence/presence of expression. iGluR are too ubiquitously expressed and of limited use as markers for areas or layers. A focus has been the iGluR profile of cortical interneuron types. For instance, GluK1 and GluN3A are enriched in, but not specific for, interneurons; moreover, the interneurons expressing these subunits belong to different types. Adressing the types is still a major hurdle because type-specific markers are lacking, and the frequently used neuropeptide/CaBP signatures are subject to regulation by age and activity and vary as well between species and areas. RNA-seq reveals almost all subunits in the two morphofunctionally characterized interneuron types of adult cortical layer I, suggesting a fairly broad expression at the RNA level. It remains to be determined whether all proteins are synthesized, to which pre- or postsynaptic subdomains in a given neuron type they localize, and whether all are involved in synaptic transmission. J. Comp. Neurol. 525:976-1033, 2017. © 2016 Wiley Periodicals, Inc.

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Development of NMDA NR2 subunits and their roles in critical period maturation of neocortical GABAergic interneurons

Cited by 52 publications

References 162 publications

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

Cell class-specific regulation of neocortical dendrite and spine growth by AMPA receptor splice and editing variants

Ionotropic glutamate receptors: Which ones, when, and where in the mammalian neocortex

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