TNF-Mediated Homeostatic Synaptic Plasticity: From in vitro to in vivo Models

Heir, Renu; Stellwagen, David

doi:10.3389/fncel.2020.565841

Cited by 71 publications

(81 citation statements)

References 116 publications

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“…Cytokines such as CXCL10 and TNF, that were found to be upregulated in the pathway analysis are secreted by microglia and exert several downstream effects not only on immune regulation, but also, in the case of TNF, on synaptic plasticity, neurogenesis and astrocyte function 51 . For example, it has been shown that TNF changes AMPA receptor current 52 similar to what we saw in our earlier work 26 . TNF is also an important molecule in cellular immunity, in particular T cell function 53 and it is no surprise that we found it to be the most activated gene for the causal network.…”

Section: Discussionsupporting

confidence: 87%

Characterization of microglial transcriptomes in the brain and spinal cord of mice in early and late experimental autoimmune encephalomyelitis using a RiboTag strategy

Acharjee

Gordon

Lee

et al. 2021

Sci Rep

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Microglia play an important role in the pathogenesis of multiple sclerosis and the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). To more fully understand the role of microglia in EAE we characterized microglial transcriptomes before the onset of motor symptoms (pre-onset) and during symptomatic EAE. We compared the transcriptome in brain, where behavioral changes are initiated, and spinal cord, where damage is revealed as motor and sensory deficits. We used a RiboTag strategy to characterize ribosome-bound mRNA only in microglia without incurring possible transcriptional changes after cell isolation. Brain and spinal cord samples clustered separately at both stages of EAE, indicating regional heterogeneity. Differences in gene expression were observed in the brain and spinal cord of pre-onset and symptomatic animals with most profound effects in the spinal cord of symptomatic animals. Canonical pathway analysis revealed changes in neuroinflammatory pathways, immune functions and enhanced cell division in both pre-onset and symptomatic brain and spinal cord. We also observed a continuum of many pathways at pre-onset stage that continue into the symptomatic stage of EAE. Our results provide additional evidence of regional and temporal heterogeneity in microglial gene expression patterns that may help in understanding mechanisms underlying various symptomology in MS.

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Section: Discussionsupporting

confidence: 87%

Characterization of microglial transcriptomes in the brain and spinal cord of mice in early and late experimental autoimmune encephalomyelitis using a RiboTag strategy

Acharjee

Gordon

Lee

et al. 2021

Sci Rep

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“…Age-dependent decline in dopamine-dependent cognition and movement is observed in humans [55][56][57]70 , non-human primates 71 , and rodents 40,60 , supporting the idea of perturbed synaptic function within this circuitry. The cytokines we find to be elevated within the VTA, TNFα and IL-1β, have both been shown to influence key aspects of glutamatergic and GABAergic synapse receptor composition, function, and placticity 72,73 . Finally, lifestyle manipulations that alter microglial phenotype and reduce inflammation, are correlated with improved cognition during aging 74,75 .…”

Section: Chronic Local Inflammation As One Consequence Of Microglial Proliferation During Aging?mentioning

confidence: 70%

“…Lifestyle manipulations such as exercise and low-fat diet that alter microglial phenotype and reduce inflammation are also associated with improved cognition 73 . Moreover, microglial TNFα has been shown to influence presynaptic probability of release and insertion/removal of postsynaptic AMPA receptors at glutamatergic synapses 83 . TNFα can also impact GABA receptor insertion/removal from inhibitory synapse, placing this molecule in a position to influence the overall balance of excitatory and inhibitory input to neurons.…”

Section: Discussionmentioning

confidence: 99%

Microglia drive pockets of neuroinflammation in middle age

Moca

Lecca

Hope

et al. 2021

Preprint

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Microglia maintain tissue health and can critically influence synaptic connectivity and function. During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to insults. In addition, risk genes for neurodegenerative disease are highly expressed by microglia. These findings argue that microglial function is likely to critically shape vulnerability or resilience of neurons during aging. We recently discovered that microglia in the ventral tegmental area (VTA) of young adult mice differ markedly from their counterparts in other brain regions. Whether this regional variation in microglia persists, diminishes, or increases during aging has not been determined. Here, we analyze microglia in several nuclei of the basal ganglia throughout the lifespan in mice and find that VTA microglia exhibit increased proliferation and production of inflammatory factors months prior to microglia in other basal ganglia nuclei. Comparable early proliferative responses were observed in the substantia nigra pars compacta where disease-vulnerable dopamine neurons reside. These proliferative and inflammatory responses of VTA microglia began as early at 13 months of age in mice and were not accompanied by substantial neuronal loss or changes in local astrocyte number. Finally, these region-specific responses of microglia to aging were enhanced by knockout of the fractalkine receptor (CX3CR1) and reduced by microglial ablation and repopulation, identifying two signaling axes by which region-specific responses of microglia to aging can be modulated. Collectively, these findings indicate that VTA and SNc microglia continue to differ from their counterparts in other basal ganglia nuclei during aging. Moreover, the early phenotypic changes in these cells result in local inflammation near dopamine neurons beginning in middle age, which may be linked to enhanced vulnerability of these neurons to functional decline and degenerative disease.

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“…Indeed, TNF-α activates glutamatergic synaptic transmission by increasing presynaptic activity, postsynaptic AMPAR trafficking and synaptic insertion, while at the same time, suppressing inhibitory synaptic transmission [ 41 , 125 ]. Further, TNF-α has been implicated in homeostatic (non-Hebbian) synaptic scaling, through its ability to regulate the quantity of synaptic AMPA receptors, as well as by synaptic pruning by controlling the phagocytosis capacity of microglia [ 47 , 125 ]. Similarly, the multi-protein complex, called the inflammasome, that controls the secretion of the pro-inflammatory cytokines, IL-1β and IL-18, is also thought to regulate synaptic pruning and play a role in neuronal survival [ 134 ].…”

Section: Main Textmentioning

confidence: 99%

Neuroimmune multi-hit perspective of coronaviral infection

Hayley

Sun

2021

J Neuroinflammation

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It is well accepted that environmental stressors experienced over a one’s life, from microbial infections to chemical toxicants to even psychological stressors, ultimately shape central nervous system (CNS) functioning but can also contribute to its eventual breakdown. The severity, timing and type of such environmental “hits”, woven together with genetic factors, likely determine what CNS outcomes become apparent. This focused review assesses the current COVID-19 pandemic through the lens of a multi-hit framework and disuses how the SARS-COV-2 virus (causative agent) might impact the brain and potentially interact with other environmental insults. What the long-term consequences of SAR2 COV-2 upon neuronal processes is yet unclear, but emerging evidence is suggesting the possibility of microglial or other inflammatory factors as potentially contributing to neurodegenerative illnesses. Finally, it is critical to consider the impact of the virus in the context of the substantial psychosocial stress that has been associated with the global pandemic. Indeed, the loneliness, fear to the future and loss of social support alone has exerted a massive impact upon individuals, especially the vulnerable very young and the elderly. The substantial upswing in depression, anxiety and eating disorders is evidence of this and in the years to come, this might be matched by a similar spike in dementia, as well as motor and cognitive neurodegenerative diseases.

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TNF-Mediated Homeostatic Synaptic Plasticity: From in vitro to in vivo Models

Cited by 71 publications

References 116 publications

Characterization of microglial transcriptomes in the brain and spinal cord of mice in early and late experimental autoimmune encephalomyelitis using a RiboTag strategy

Characterization of microglial transcriptomes in the brain and spinal cord of mice in early and late experimental autoimmune encephalomyelitis using a RiboTag strategy

Microglia drive pockets of neuroinflammation in middle age

Neuroimmune multi-hit perspective of coronaviral infection

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