Differential Regulation of AMPA Receptor and GABA Receptor Trafficking by Tumor Necrosis Factor-α

Stellwagen, David; Beattie, Eric C.; Seo, Jae Y.; Malenka, Robert C.

doi:10.1523/jneurosci.4486-04.2005

Cited by 881 publications

(803 citation statements)

References 68 publications

Supporting

Mentioning

731

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, several groups have reported a role for TNFα as a regulator of surface AMPAR expression in spinal cord motor neurons. These studies have shown that TNFα triggers a change in AMPARs which can promote a shift towards surface expression of GluA2‐lacking receptors (Ferguson et al, 2008; Ogoshi et al, 2005; Stellwagen, 2005). Although these studies focused on the rapid effects of short‐term TNFα exposure, we have demonstrated here that longer incubations with TNFα–containing mutFUS‐ACM, not only alter GluA1 & GluA2 protein levels but also trigger an increase mRNA levels for GluA1.…”

Section: Discussionmentioning

confidence: 99%

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

View full text Add to dashboard Cite

Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation. Time lapse imaging shows that motor neuron cultures exposed to mutFUS ACM, but not WTFUS ACM, undergo significant cell loss, which is preceded by progressive degeneration of neurites. We found that Tumor Necrosis Factor‐Alpha (TNFα) is secreted into ACM of mutFUS‐expressing astrocytes. Accordingly, mutFUS astrocyte‐mediated motor neuron toxicity is blocked by targeting soluble TNFα with neutralizing antibodies. We also found that mutant astrocytes trigger changes to motor neuron AMPA receptors (AMPAR) that render them susceptible to excitotoxicity and AMPAR‐mediated cell death. Our data provide the first evidence of astrocytic involvement in FUS‐ALS, identify TNFα as a mediator of this toxicity, and provide several potential therapeutic targets to protect motor neurons in FUS‐linked ALS.

show abstract

Section: Discussionmentioning

confidence: 99%

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

View full text Add to dashboard Cite

show abstract

“…TLR4 activation triggers a cascade of signaling events leading to the release of many proinflammatory cytokines. These cytokines, such as tumor necrosis factor-a and interleukin-1b, not only exert their excitatory effects via upregulating excitatory synaptic transmission [30,31], but also regulate neuronal functions via interacting with modulatory systems [32]. All these TLR4-mediated molecular and cellular consequences are pivotal to relevant neuropsychiatric diseases.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Yan

Cheng

et al. 2016

Neurosci. Bull.

View full text Add to dashboard Cite

Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine (DA) system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4 (TLR4), an important pattern-recognition receptor in the innate immune system, can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient (TLR4 -/-) and wild-type (WT) mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed, large spaces. We found that TLR4 -/-mice exhibited reduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4 -/-mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approachavoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4 -/-mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly, the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell (NAcSh) in TLR4 -/-mice than in WT mice. Partially inactivating the NAcSh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4 -/-mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAcSh may contribute to this phenomenon.

show abstract

“…TNFR receptor activation increases α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) trafficking to the membrane surface of neurons while decreasing GABAa receptor surface expression [31]. These TNFR signalling effects were mediated by increases in the amplitude and frequency of mEPSCs and decreases in the amplitude of mIPSCs [29,32]. Direct inhibition of endogenous TNF-α could also bring about these effects on AMPARs [29,33].…”

Section: Tnf-α and Synaptic Signallingmentioning

confidence: 99%

Targeting tumour necrosis factor-α in hypoxia and synaptic signalling

O’Connor

2013

Ir J Med Sci

View full text Add to dashboard Cite

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine, which is synthesised and released in the brain by astrocytes, microglia and neurons in response to numerous internal and external stimuli. It is involved in many physiological and pathophysiological processes such as gene transcription, cell proliferation, apoptosis, synaptic signalling and neuroprotection. The complex actions of TNF-α in the brain are under intense investigation. TNF-α has the ability to induce selective necrosis of some cells whilst sparing others and this has led researchers to discover multiple activated signalling cascades. In many human diseases including acute stroke and inflammation and those involving hypoxia, levels of TNF-α are increased throughout different brain regions. TNF-α signalling may also have several positive and negative effects on neuronal function including glutamatergic synaptic transmission and plasticity. Exogenous TNF-α may also exacerbate the neuronal response to hypoxia. This review will summarise the actions of TNF-α in the central nervous system on synaptic signalling and its effects during hypoxia.

show abstract

Differential Regulation of AMPA Receptor and GABA Receptor Trafficking by Tumor Necrosis Factor-α

Cited by 881 publications

References 68 publications

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Targeting tumour necrosis factor-α in hypoxia and synaptic signalling

Contact Info

Product

Resources

About