Stepwise disassembly of GABAergic synapses during pathogenic excitotoxicity

Garcia, Joshua D.; Gookin, Sara E.; Crosby, Kevin C.; Schwartz, Samantha L.; Tiemeier, Erika; Kennedy, Matthew J.; Dell’Acqua, Mark L.; Herson, Paco S.; Quillinan, Nidia; Smith, Katharine R.

doi:10.1016/j.celrep.2021.110142

Cited by 26 publications

(50 citation statements)

References 83 publications

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“…NMDARs and LTCCs each activate signaling pathways controlling both rapid changes at synapses that occur within sec-min of plasticity induction as well as subsequent long-lasting changes in gene expression that are required to maintain plasticity expression over hrs-days ( Catterall, 2011 ; Dolmetsch, 2003 ; Greer and Greenberg, 2008 ; Grover and Teyler, 1990 ; Langwieser et al, 2010 ; Moosmang et al, 2005 ; Rajgor et al, 2020 ; Wild et al, 2019 ). In particular, during plasticity induction membrane depolarization generated by NMDARs and AMPARs can open LTCCs to mediate rapid Ca 2+ -dependent signaling events controlling postsynaptic AMPAR and GABA A R trafficking, LTP expression, and structural remodeling of dendritic spines ( Dittmer et al, 2017 , 2019 ; Garcia et al, 2021 ; Hiester et al, 2017 ; Moosmang et al, 2005 ; Qian et al, 2012 , 2017 ), as well as long-term changes in gene transcription that support plasticity maintenance ( Deisseroth et al, 1996 ; Graef et al, 1999 ; Kang et al, 2001 ; Li et al, 2012 , 2016 ; Ma et al, 2014 ; Mermelstein et al, 2000 ; Murphy et al, 2014 , 2019 ; Oliveria et al, 2007 ; Rajgor et al, 2020 ; Wheeler et al, 2008 , 2012 ; Wild et al, 2019 ; Wu et al, 2001 ).…”

Section: Discussionmentioning

confidence: 99%

The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome

et al. 2022

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Section: Discussionmentioning

confidence: 99%

The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome

et al. 2022

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“…In this model, group 1 mGluRs promote IP3R-dependent intracellular calcium store release from the endoplasmic reticulum, leading to PKC-mediated GABA A R stabilization. Conversely, NMDAR-induced calcium influx activates the phosphatase calcineurin, which dephosphorylates γ2-GABA A Rs at S327, resulting in enhanced GABA A R mobility required for the rapid induction of iLTD during elevated activity ( Lu Y. M. et al, 2000 ; Wang et al, 2003 ; Muir et al, 2010 ; Bannai et al, 2015 ; Garcia et al, 2021 ). Pharmacological inhibition of NMDAR (APV), group 1 mGluR (MPEP and CPCCOEt), IP3R (Xestospongin C), or calcineurin (FK506) all prevent heterosynaptic eLTD, strongly supporting the role of these calcium signaling pathways in eLTD ( Oh et al, 2015 ; Tong et al, 2021 ).…”

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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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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“…In this context, the administration of GLP-1RAs (e.g., exendin-4 and liraglutide) prior to or following cerebral ischaemia in animal models of stroke have consistently been reported to reduce infarct size, mitigate oxidative stress and improve endothelial function [38,39,54,61,63]. The neuroinflammatory cascade following the excitotoxic insults within the CNS also affect GABA receptor-mediated inhibitory signalling by eliminating GABAergic synapses, thus exacerbating the imbalance in the neuronal excitation/inhibition and possibly contributing to the NVU dysfunction (i.e., BBB disruption) [232]. Intriguingly, pancreatic β-cells are among the extra-neural sites expressing high levels of glutamate decarboxylase, an enzyme that catalyses the formation of GABA from glutamate [233,234].…”

Section: Effects Of Glp1-ras At the Nvumentioning

confidence: 99%

GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight

Monti

Moreira

Richner

et al. 2022

Cells

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Defects in brain energy metabolism and proteopathic stress are implicated in age-related degenerative neuronopathies, exemplified by Alzheimer’s disease (AD) and Parkinson’s disease (PD). As the currently available drug regimens largely aim to mitigate cognitive decline and/or motor symptoms, there is a dire need for mechanism-based therapies that can be used to improve neuronal function and potentially slow down the underlying disease processes. In this context, a new class of pharmacological agents that achieve improved glycaemic control via the glucagon-like peptide 1 (GLP-1) receptor has attracted significant attention as putative neuroprotective agents. The experimental evidence supporting their potential therapeutic value, mainly derived from cellular and animal models of AD and PD, has been discussed in several research reports and review opinions recently. In this review article, we discuss the pathological relevance of derangements in the neurovascular unit and the significance of neuron–glia metabolic coupling in AD and PD. With this context, we also discuss some unresolved questions with regard to the potential benefits of GLP-1 agonists on the neurovascular unit (NVU), and provide examples of novel experimental paradigms that could be useful in improving our understanding regarding the neuroprotective mode of action associated with these agents.

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Stepwise disassembly of GABAergic synapses during pathogenic excitotoxicity

Cited by 26 publications

References 83 publications

The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome

The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome

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

GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight

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