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

By D. Stellwagen, E. Beattie, J. Seo, R. Malenka. Journal of Neuroscience, 2005

910 citations recorded by the source corpus.

The proinflammatory cytokine tumor necrosis factor-α (TNFα) causes a rapid exocytosis of AMPA receptors in hippocampal pyramidal cells and is constitutively required for the maintenance of normal surface expression of AMPA receptors. Here we demonstrate that TNFα acts on neuronal TNFR1 receptors to preferentially exocytose glutamate receptor 2-lacking AMPA receptors through a phosphatidylinositol 3 kinase-dependent process. This increases excitatory synaptic strength while changing the molecular stoichiometry of synaptic AMPA receptors. Conversely, TNFα causes an endocytosis of GABAA receptors, resulting in fewer surface GABAA receptors and a decrease in inhibitory synaptic strength. These results suggest that TNFα can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/c5103a200e7788d81255b31b43570f46e6594e9c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Gina G. Turrigiano
2. A. Citri
3. G. Davis
4. R. Malenka
5. R. Ji
6. A. Vezzani
7. Beth Stevens
8. Wulfram Gerstner

In Molecular Biology

1. G. Davis
2. R. Malenka
3. Gina G. Turrigiano
4. A. Citri
5. R. Ji
6. Beth Stevens
7. Alberto E. Musto
8. Amna Rana

In Neurology

1. Gina G. Turrigiano
2. A. Citri
3. G. Davis
4. A. Vezzani
5. R. Ji
6. Beth Stevens
7. R. Malenka
8. B. Barres

Citations in the corpus

• Astrocytes Control Synapse Formation, Function, and Elimination (2015, neutral): “Interestingly, TNF-a has the opposite effect on GABAARs, causing a decrease in the surface levels of these inhibitory receptors (Stellwagen et al. 2005).”
• The role of inflammation in the development of epilepsy (2018, background): “TNF-α not only amplifies the number of glutamate receptors but also induces GABA receptor endocytosis, reducing the inhibitory drive and causing pertinent changes in excitability [26].”
• Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms (2008, background): “Specifically, secretion of the proinflammatory cytokine tumor necrosis factor-a from glial cells appears to be necessary for the increase in the level of synaptic AMPARs caused by extended periods of activity blockade (Beattie et al, 2002; Stellwagen et al, 2005; Stellwagen and Malenka, 2006).”
• Homeostatic control of neural activity: from phenomenology to molecular design. (2006, background): “For example, TNF-alpha can induce a dramatic increase in the surface expression of glutamate receptors in cultured hippocampal neurons, and glial-derived TNF-alpha is necessary for quantal scaling in vitro (Beattie et al. 2002, Stellwagen et al. 2005; Stellwagen & Malenka 2006).”
• Cytokine Mechanisms of Central Sensitization: Distinct and Overlapping Role of Interleukin-1β, Interleukin-6, and Tumor Necrosis Factor-α in Regulating Synaptic and Neuronal Activity in the Superficial Spinal Cord (2008, result): “TNFα also enhanced AMPA-induced current in dorsal horn neurons, in agreement with a previous report from hippocampal neurons (Stellwagen et al., 2005).”
• Immune modulation of learning, memory, neural plasticity and neurogenesis. (2011, neutral): “AMPA receptors have abnormal stoichiometry, as they lack the GluR2 subunit; thus, they become Ca2+ permeable and may contribute to neurotoxicity (Stellwagen et al., 2005).”
• Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement. (2011, background): “Indeed, experimenters have now uncovered a rich variety of homeostatic synaptic mechanisms that operate on both excitatory and inhibitory synapses, which I describe below in turn.”
• Brain Inflammation in Epilepsy: Experimental and Clinical Evidence (2005, background): “Conversely, TNF-α causes endocytosis of GABAA receptors, thus resulting in decreased inhibitory strength (27,82).”
• Microglia: Dynamic Mediators of Synapse Development and Plasticity (2015, background): “However, in the striatum, TNF/ signaling that was upregulated by application of dopamine D2 receptor antagonists led to a reduction of calcium-permeable AMPA receptors [31,32].”