Tumor necrosis factor‐α potentiates long‐term potentiation in the rat dentate gyrus after acute hypoxia

Wall, Audrey; Mukandala, Gatambwa; Greig, Nigel H.; O’Connor, John

doi:10.1002/jnr.23540

Cited by 32 publications

(23 citation statements)

References 61 publications

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“…Though others have previously shown that TNFα can facilitate LTP in hippocampal slices under certain conditions [ 56 ], consistent with our findings, several earlier studies reported an impairment in LTP induction in both the dentate and the CA1 regions of the hippocampus following exogenous application of pathophysiological quantities of TNFα [ 27 – 29 ]. These apparent discrepancies may be attributable to several fundamental methodological differences.…”

Section: Discussionsupporting

confidence: 93%

The TNFα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss

Pettigrew

Norris

2016

PLoS ONE

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The cytokine, tumor necrosis factor α (TNFα), is a key regulator of neuroinflammation linked to numerous neurodegenerative conditions and diseases. The present study used transgenic rats that overexpress a murine TNFα gene, under the control of its own promoter, to investigate the impact of chronically elevated TNFα on hippocampal synaptic function. Neuronal viability and cognitive recovery in TNFα Tg rats were also determined following an ischemic insult arising from reversible middle cerebral artery occlusion (MCAO). Basal CA3-CA1 synaptic strength, recorded in acute brain slices, was not significantly different between eight-week-old TNFα Tg rats and non-Tg rats. In contrast, slices from TNFα Tg rats showed significantly greater levels of long-term potentiation (LTP) in response to 100 Hz stimulation, suggesting that synaptic networks may be hyperexcitable in the context of elevated TNFα. Cognitive and motor deficits (assessed on the Morris Water Maze and Rotarod task, respectively) were present in TNFα Tg rats in the absence of significant differences in the loss of cortical and hippocampal neurons. TNF overexpression exacerbated MCAO-dependent deficits on the rotarod, but ameliorated cortical neuron loss in response to MCAO.

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Section: Discussionsupporting

confidence: 93%

The TNFα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss

Pettigrew

Norris

2016

PLoS ONE

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“…There are many factors regulating the magnitude of LTP induced by different parameters such as high frequency stimulation and theta burst stimulation [ 101 ] ( Figure 3 ). Recently, we have shown that the stimulation parameters used to induce LTP may have an influence on TNF-α’s ability to inhibit LTP [ 102 ]. TNF-α has no inhibitory effect on LTP when induced with prolonged high frequency stimulation (HFS) whereas full inhibition was observed when LTP was induced by theta burst stimulation (TBS).…”

Section: Tnf-α and Synaptic Plasticitymentioning

confidence: 99%

“…All these effects by TNF-α result in the increase in the concentration of glutamate in the synaptic cleft, which may have an influence on the magnitude of LTP post-hypoxia. Using a robust LTP-inducing stimulus protocol we have been able to demonstrate a significant enhancing effect of TNF-α on LTP post hypoxia but only in the dentate gyrus of the hippocampus [ 102 ]. In the presence of DMOG (a non-specific PHD inhibitor) this enhancement of LTP was still evident perhaps indicating a novel HIF/PHD-independent effect of TNF-α [ 102 ].…”

Section: Tnf-α Hypoxia and Synaptic Plasticitymentioning

confidence: 99%

The Effects of Hypoxia and Inflammation on Synaptic Signaling in the CNS

Mukandala¹,

Tynan²,

Lanigan³

et al. 2016

Brain Sciences

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117

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Normal brain function is highly dependent on oxygen and nutrient supply and when the demand for oxygen exceeds its supply, hypoxia is induced. Acute episodes of hypoxia may cause a depression in synaptic activity in many brain regions, whilst prolonged exposure to hypoxia leads to neuronal cell loss and death. Acute inadequate oxygen supply may cause anaerobic metabolism and increased respiration in an attempt to increase oxygen intake whilst chronic hypoxia may give rise to angiogenesis and erythropoiesis in order to promote oxygen delivery to peripheral tissues. The effects of hypoxia on neuronal tissue are exacerbated by the release of many inflammatory agents from glia and neuronal cells. Cytokines, such as TNF-α, and IL-1β are known to be released during the early stages of hypoxia, causing either local or systemic inflammation, which can result in cell death. Another growing body of evidence suggests that inflammation can result in neuroprotection, such as preconditioning to cerebral ischemia, causing ischemic tolerance. In the following review we discuss the effects of acute and chronic hypoxia and the release of pro-inflammatory cytokines on synaptic transmission and plasticity in the central nervous system. Specifically we discuss the effects of the pro-inflammatory agent TNF-α during a hypoxic event.

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“…These results suggest an important role for TNF-a signaling in modulation of EphB2 expression. TNF-a has been shown to be involved in synaptic plasticity (Marchetti et al, 2004;Pickering et al, 2005;Belarbi et al, 2012;Wall et al, 2015), but a connection to EphB2 has not yet been established in human neurons.…”

Section: Journal Of Cellular Physiology T N F -A a C T I V A T I O N mentioning

confidence: 99%

TNF‐α/TNFR2 Regulatory Axis Stimulates EphB2‐Mediated Neuroregeneration Via Activation of NF‐κB

Pozniak

Darbinyan

Khalili

2015

Journal Cellular Physiology

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HIV-1 infected individuals are at high risk of developing HIV-associated neurocognitive disorders (HAND) as HIV infection leads to neuronal injury and synaptic loss in the central nervous system (CNS). The neurotoxic effects of HIV-1 are primarily a result of viral replication leading to the production of inflammatory chemokines and cytokines, including TNF-alpha. Given an important role of TNF-alpha in regulating synaptic plasticity, we investigated the effects of TNF-alpha on the development of neuronal processes after mechanical injury, and we showed that TNF-alpha treatment stimulates the regrowth of neuronal processes. To investigate transcriptional effects of TNF-alpha on synaptic plasticity, we analyzed both human neurosphere and isolated neuronal cultures for the regulation of genes central to synaptic alterations during learning and memory. TNF-alpha treatment upregulated Ephrin receptor B2 (EphB2), which is strongly involved in dendritic arborization and synaptic integrity. TNF-alpha strongly activates the NF-kappaB pathway, therefore, we propose that TNF-alpha-induced neurite regrowth occurs primarily through EphB2 signaling via stimulation of NF-kappaB. EphB2 promoter activity increased with TNF-alpha treatment and overexpression of NF-kappaB. Direct binding of NF-kappaB to the EphB2 promoter occurred in the ChIP assay, and site-directed mutagenesis identified binding sites involved in TNF-alpha-induced EphB2 activation. TNF-alpha induction of EphB2 was determined to occur specifically through TNF-alpha receptor 2 (TNFR2) activation in human primary fetal neurons. Our observations provide a new avenue for the investigation on the impact of TNF-alpha in the context of HIV-1 neuronal cell damage as well as providing a potential therapeutic target in TNFR2 activation of EphB2.

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Tumor necrosis factor‐α potentiates long‐term potentiation in the rat dentate gyrus after acute hypoxia

Cited by 32 publications

References 61 publications

The TNFα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss

The TNFα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss

The Effects of Hypoxia and Inflammation on Synaptic Signaling in the CNS

TNF‐α/TNFR2 Regulatory Axis Stimulates EphB2‐Mediated Neuroregeneration Via Activation of NF‐κB

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