Synaptic and Network Contributions to Anoxic Depolarization in Mouse Hippocampal Slices

Heit, Bradley S; Dykas, Patricia; Chu, Alex; Sane, Abhay; Larson, John

doi:10.1016/j.neuroscience.2021.02.021

Cited by 7 publications

(20 citation statements)

References 56 publications

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“…Because WT slices reached AD earlier, xCT −/− slices remained in the depolarized state for shorter epochs relative to WT slices. Importantly, the time between AD and re-oxygenation strongly influences recovery (Heit et al, 2021); hence, it is not surprising that xCT −/− slices showed improved recovery of fEPSPs (55.640 ± 21.950% of pre-anoxia baseline) compared to WT slices We therefore sought to determine if recovery of synaptic transmission would differ between genotypes when the time between AD and re-oxygenation was held constant. As such, we performed anoxia experiments where xCT −/− or WT slices were individually subjected to anoxia, measured for latency to anoxic depolarization, left in the depolarized state for 60 s, then fully re-oxygenated and allowed to recover for 45 min.…”

Section: Resultsmentioning

confidence: 99%

“…Again, the AD event is predominantly precipitated by the activation of NMDARs (Fusco et al, 2018;Heit et al, 2021), and therefore CPG proved to be the best option for this investigation. We first ran separate paired experiments to assess whether 2.0 h of CPG administration would affect normal synaptic transmission in WT and/or xCT −/− slices.…”

Section: Reproduces Effect Of Xct Ko On Admentioning

confidence: 99%

“…Importantly, it has become widely accepted that the AD event is the spark that ignites the neurotoxic sequelae leading to cell death (Ayata, 2018 ; Hartings et al., 2017 ; Leão 1947 ), and the evidence indicates that the timing of AD relative to the onset of anoxia/ischaemia and to the onset of re‐oxygenation/reperfusion are critical factors in ischaemic brain damage (Jarvis et al., 2001 ; Kaminogo et al., 1998 ; Kostandy, 2012 ). Shorter AD latencies lead to increased damage (Douglas et al., 2011 ; Obeidat & Andrew, 1998 ; Weber & Taylor, 1994 ) whereas shorter delays between AD and re‐oxygenation enhance recovery (Heit et al., 2021 ). Attenuating the accumulation of excessive extracellular glutamate, which drives AD, is therefore a critical objective for the development of successful therapies.…”

Section: Introductionmentioning

confidence: 99%

“…Attenuating the accumulation of excessive extracellular glutamate, which drives AD, is therefore a critical objective for the development of successful therapies. Although prior reports have demonstrated the efficacy of glutamate receptor antagonists in mitigating the ischaemic cascade and delaying AD (Aitken et al., 1988 ; Fusco et al., 2018 ; Heit et al., 2021 ; Roberts et al., 1998 ), efforts to produce effective interventions for the human condition have been plagued by translational failure due to contraindications resulting from synaptic inhibition of glutamatergic transmission.…”

Section: Introductionmentioning

confidence: 99%

“…The present study therefore examined the contribution of system x c − and its regulation of ambient glutamate levels to the timing of anoxic depolarization in an acute in vitro model of stroke: hippocampal slices subjected to oxygen deprivation. This model has been extensively used to study the early electrophysiological events in ischaemia (Arrigoni et al., 2005 ; Coelho et al., 2006 ; Croning & Haddad, 1998 ; Dale et al., 2000 ; Fischer et al., 2009 ; Heit et al., 2021 ; Lipton, 1999 ; Pearson & Frenguelli, 2004 ; Wang et al., 1999 ) and replicates the pathophysiological time course of human stroke with fidelity (Dreier et al., 2018 ). The experiments used wild‐type (WT) and xCT −/− mice, as well as a pharmacological inhibitor of system x c − .…”

Section: Introductionmentioning

confidence: 99%

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Tonic extracellular glutamate and ischaemia: glutamate antiporter system x_c⁻ regulates anoxic depolarization in hippocampus

Heit

Chu

Sane

et al. 2022

The Journal of Physiology

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In stroke, the sudden deprivation of oxygen to neurons triggers a profuse release of glutamate that induces anoxic depolarization (AD) and leads to rapid cell death. Importantly, the latency of the glutamate‐driven AD event largely dictates subsequent tissue damage. Although the contribution of synaptic glutamate during ischaemia is well‐studied, the role of tonic (ambient) glutamate has received far less scrutiny. The majority of tonic, non‐synaptic glutamate in the brain is governed by the cystine/glutamate antiporter, system xc−. Employing hippocampal slice electrophysiology, we showed that transgenic mice lacking a functional system xc− display longer latencies to AD and altered depolarizing waves compared to wild‐type mice after total oxygen deprivation. Experiments which pharmacologically inhibited system xc−, as well as those manipulating tonic glutamate levels and those antagonizing glutamate receptors, revealed that the antiporter's putative effect on ambient glutamate precipitates the ischaemic cascade. As such, the current study yields novel insight into the pathogenesis of acute stroke and may direct future therapeutic interventions. Key points Ischaemic stroke remains the leading cause of adult disability in the world, but efforts to reduce stroke severity have been plagued by failed translational attempts to mitigate glutamate excitotoxicity. Elucidating the ischaemic cascade, which within minutes leads to irreversible tissue damage induced by anoxic depolarization, must be a principal focus. Data presented here show that tonic, extrasynaptic glutamate supplied by system xc− synergizes with ischaemia‐induced synaptic glutamate release to propagate AD and exacerbate depolarizing waves. Exploiting the role of system xc− and its obligate release of ambient glutamate could, therefore, be a novel therapeutic direction to attenuate the deleterious effects of acute stroke.

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Section: Resultsmentioning

confidence: 99%

Section: Reproduces Effect Of Xct Ko On Admentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tonic extracellular glutamate and ischaemia: glutamate antiporter system x_c⁻ regulates anoxic depolarization in hippocampus

Heit

Chu

Sane

et al. 2022

The Journal of Physiology

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Cerebral Hypoxia-Induced Molecular Alterations and Their Impact on the Physiology of Neurons and Dendritic Spines: A Comprehensive Review

Cui,

Jiang,

Wang

et al. 2024

Cell Mol Neurobiol

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This article comprehensively reviews how cerebral hypoxia impacts the physiological state of neurons and dendritic spines through a series of molecular changes, and explores the causal relationship between these changes and neuronal functional impairment. As a severe pathological condition, cerebral hypoxia can significantly alter the morphology and function of neurons and dendritic spines. Specifically, dendritic spines, being the critical structures for neurons to receive information, undergo changes such as a reduction in number and morphological abnormalities under hypoxic conditions. These alterations further affect synaptic function, leading to neurotransmission disorders. This article delves into the roles of molecular pathways like MAPK, AMPA receptors, NMDA receptors, and BDNF in the hypoxia-induced changes in neurons and dendritic spines, and outlines current treatment strategies. Neurons are particularly sensitive to cerebral hypoxia, with their apical dendrites being vulnerable to damage, thereby affecting cognitive function. Additionally, astrocytes and microglia play an indispensable role in protecting neuronal and synaptic structures, regulating their normal functions, and contributing to the repair process following injury. These studies not only contribute to understanding the pathogenesis of related neurological diseases but also provide important insights for developing novel therapeutic strategies. Future research should further focus on the dynamic changes in neurons and dendritic spines under hypoxic conditions and their intrinsic connections with cognitive function.

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Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice

Escobar

Jackson

et al. 2023

Neurotherapeutics

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Perturbations in synaptic function are major determinants of several neurological diseases and have been associated with cognitive impairments after cerebral ischemia (CI). Although the mechanisms underlying CI-induced synaptic dysfunction have not been well defined, evidence suggests that early hyperactivation of the actin-binding protein, cofilin, plays a role. Given that synaptic impairments manifest shortly after CI, prophylactic strategies may offer a better approach to prevent/mitigate synaptic damage following an ischemic event. Our laboratory has previously demonstrated that resveratrol preconditioning (RPC) promotes cerebral ischemic tolerance, with many groups highlighting beneficial effects of resveratrol treatment on synaptic and cognitive function in other neurological conditions. Herein, we hypothesized that RPC would mitigate hippocampal synaptic dysfunction and pathological cofilin hyperactivation in an ex vivo model of ischemia. Various electrophysiological parameters and synaptic-related protein expression changes were measured under normal and ischemic conditions utilizing acute hippocampal slices derived from adult male mice treated with resveratrol (10 mg/kg) or vehicle 48 h prior. Remarkably, RPC significantly increased the latency to anoxic depolarization, decreased cytosolic calcium accumulation, prevented aberrant increases in synaptic transmission, and rescued deficits in long-term potentiation following ischemia. Additionally, RPC upregulated the expression of the activity-regulated cytoskeleton associated protein, Arc, which was partially required for RPC-mediated attenuation of cofilin hyperactivation. Taken together, these findings support a role for RPC in mitigating CI-induced excitotoxicity, synaptic dysfunction, and pathological over-activation of cofilin. Our study provides further insight into mechanisms underlying RPC-mediated neuroprotection against CI and implicates RPC as a promising strategy to preserve synaptic function after ischemia.

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Synaptic and Network Contributions to Anoxic Depolarization in Mouse Hippocampal Slices

Cited by 7 publications

References 56 publications

Tonic extracellular glutamate and ischaemia: glutamate antiporter system x_c⁻ regulates anoxic depolarization in hippocampus

Tonic extracellular glutamate and ischaemia: glutamate antiporter system x_c⁻ regulates anoxic depolarization in hippocampus

Cerebral Hypoxia-Induced Molecular Alterations and Their Impact on the Physiology of Neurons and Dendritic Spines: A Comprehensive Review

Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice

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Synaptic and Network Contributions to Anoxic Depolarization in Mouse Hippocampal Slices

Cited by 7 publications

References 56 publications

Tonic extracellular glutamate and ischaemia: glutamate antiporter system xc− regulates anoxic depolarization in hippocampus

Tonic extracellular glutamate and ischaemia: glutamate antiporter system xc− regulates anoxic depolarization in hippocampus

Cerebral Hypoxia-Induced Molecular Alterations and Their Impact on the Physiology of Neurons and Dendritic Spines: A Comprehensive Review

Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice

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Product

Resources

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Tonic extracellular glutamate and ischaemia: glutamate antiporter system x_c⁻ regulates anoxic depolarization in hippocampus

Tonic extracellular glutamate and ischaemia: glutamate antiporter system x_c⁻ regulates anoxic depolarization in hippocampus