Distinct regulation of tonic GABAergic inhibition by NMDA receptor subtypes

Wu, Kunwei; Castellano, David; Tian, Qingjun; Lü, Wei

doi:10.1016/j.celrep.2021.109960

Cited by 20 publications

(8 citation statements)

References 76 publications

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“…Co-application of the AMPAR antagonist NBQX blocks these responses. Bicuculline-induced increases in surface α5-GABA A Rs and tonic inhibition after 24–48 h are also blocked by APV or the GluN2A-preferring antagonist NVP ( Wu et al, 2021a ). Activity-dependent scaling of inhibition was recently demonstrated in detail using super-resolution microscopy.…”

Section: Gaba Type a Receptor Synaptic Plasticity Induced By Pharmaco...mentioning

confidence: 99%

“…Exposure to NMDA or aspartate activates NMDARs and subsequently suppresses GABA A R current ( Stelzer and Shi, 1994 ; Chisari et al, 2012 ) in a GABA concentration-dependent manner ( Cong et al, 2011 ), and vice versa —NMDAR currents can be suppressed by GABA A R pre-activation ( Cong et al, 2011 ). Recent GluN2A vs. GluN2B NMDAR subtype-specific crosstalk effects were identified; 24-h antagonism of GluN2A in cultured neurons at days in vitro 14 (DIV14) with NVP-AAM077 decreased surface α5-GABA A R and tonic inhibition, while blockade of GluN2B with ifenprodil led to an increase ( Wu et al, 2021a ). In contrast to moderate-to-high level NMDAR activation that destabilizes GABA A R, a low-level, brief NMDAR activation results in enhanced spontaneous IPSCs ( Xue et al, 2011 ) and α5-GABA A R-mediated tonic current ( Wyroślak et al, 2021 ) while simultaneously inducing eLTD ( Rajgor et al, 2020 ).…”

Section: Interplay Between Glutamatergic and Gabaergic Synapsesmentioning

confidence: 99%

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The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

Chapman

Nuwer

Jacob

2022

Front. Synaptic Neurosci.

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Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response to changes in activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones and their functional integration within dendritic regions, concurrent plasticity has historically been underassessed. Growing evidence for pathological disruptions in the excitation and inhibition (E/I) balance in neurological and neurodevelopmental disorders indicates the need for an improved, more “holistic” understanding of synaptic interplay. There continues to be a long-standing focus on the persistent strengthening of excitation (excitatory long-term potentiation; eLTP) and its role in learning and memory, although the importance of inhibitory long-term potentiation (iLTP) and depression (iLTD) has become increasingly apparent. Emerging evidence further points to a dynamic dialogue between excitatory and inhibitory synapses, but much remains to be understood regarding the mechanisms and extent of this exchange. In this mini-review, we explore the role calcium signaling and synaptic crosstalk play in regulating postsynaptic plasticity and neuronal excitability. We examine current knowledge on GABAergic and glutamatergic synapse responses to perturbances in activity, with a focus on postsynaptic plasticity induced by short-term pharmacological treatments which act to either enhance or reduce neuronal excitability via ionotropic receptor regulation in neuronal culture. To delve deeper into potential mechanisms of synaptic crosstalk, we discuss the influence of synaptic activity on key regulatory proteins, including kinases, phosphatases, and synaptic structural/scaffolding proteins. Finally, we briefly suggest avenues for future research to better understand the crosstalk between glutamatergic and GABAergic synapses.

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Section: Gaba Type a Receptor Synaptic Plasticity Induced By Pharmaco...mentioning

confidence: 99%

Section: Interplay Between Glutamatergic and Gabaergic Synapsesmentioning

confidence: 99%

The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

Chapman

Nuwer

Jacob

2022

Front. Synaptic Neurosci.

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“…In the early literature, it has been pointed out that the loss of GABA synaptic transmission in pyramidal neurons leads to enhancement of cell excitability and promotes the opening of NMDR channels in the early stage of ischemia-reperfusion (I/R), resulting in ischemic neuronal death [ 188 ]. In addition, the GluN2-NMDA receptor subunit reverse specifically regulates the transmission of GABA in the highly activated state, showing a decrease in the expression of α5-GABAAR [ 189 ]. Because the function of GABA is opposite to that of glutamate, it can antagonize the glutamatergic activity of neurotoxicity during ischemia.…”

Section: Regulation Of Glutamatergic Transmission By Inhibitory Synapsementioning

confidence: 99%

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Fan

Xie

Xing

et al. 2022

IJMS

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Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).

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“…Part of the role of this trafficking is to allow for excitatory synapses to be strengthened in the setting of learning, and its potential cellular correlate long-term potentiation, which would not be possible if a targeted increase in excitatory glutamatergic signaling was met with a reciprocal increase in GABAergic. And yet, despite these early findings of induction of GABA A R dispersion due to NMDAR-mediated excitatory signaling, additional investigations have uncovered a potential role for NMDAR activation in inhibitory long-term potentiation (iLTP), and even inhibitory synaptogenesis ( Marsden et al, 2007 ; Petrini et al, 2014 ; Gu et al, 2016 ; Chiu et al, 2018 ; Wu et al, 2021a ).…”

Section: Gaba-a Receptor Trafficking Stabilization and Localizationmentioning

confidence: 99%

“…In immature neurons, signaling through GluN2B-containing NMDARs directly regulates the strength of tonic inhibition, whereas manipulation of those receptors with GluN2A was without effect. In contrast, in mature neurons, both GluN2B- and GluN2A containing–NMDARs serve to regulate the strength of tonic inhibition through promotion or blockade of endocytosis of α5 containing extrasynaptic GABA A Rs, respectively ( Wu et al, 2021a ).…”

Section: Gaba-a Receptor Trafficking Stabilization and Localizationmentioning

confidence: 99%

Regulation of Inhibitory Signaling at the Receptor and Cellular Level; Advances in Our Understanding of GABAergic Neurotransmission and the Mechanisms by Which It Is Disrupted in Epilepsy

Tipton

Russek

2022

Front. Synaptic Neurosci.

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Inhibitory signaling in the brain organizes the neural circuits that orchestrate how living creatures interact with the world around them and how they build representations of objects and ideas. Without tight control at multiple points of cellular engagement, the brain’s inhibitory systems would run down and the ability to extract meaningful information from excitatory events would be lost leaving behind a system vulnerable to seizures and to cognitive decline. In this review, we will cover many of the salient features that have emerged regarding the dynamic regulation of inhibitory signaling seen through the lens of cell biology with an emphasis on the major building blocks, the ligand-gated ion channel receptors that are the first transduction point when the neurotransmitter GABA is released into the synapse. Epilepsy association will be used to indicate importance of key proteins and their pathways to brain function and to introduce novel areas for therapeutic intervention.

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Distinct regulation of tonic GABAergic inhibition by NMDA receptor subtypes

Cited by 20 publications

References 76 publications

The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Regulation of Inhibitory Signaling at the Receptor and Cellular Level; Advances in Our Understanding of GABAergic Neurotransmission and the Mechanisms by Which It Is Disrupted in Epilepsy

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