Tumor necrosis factor α modulates excitatory and inhibitory neurotransmission in a concentration-dependent manner

Microglia, the brains resident immune cells, have been implicated in important brain functions, such as synaptic transmission and plasticity. The pro-inflammatory cytokine tumor necrosis factor (TNF), which is produced and secreted by microglia, has been linked to the expression of synaptic plasticity in neurons. However, the role of TNF-mediated activation of microglia has not been addressed in this context. Here, we assessed concentration-dependent effects of TNF on the balance of synaptic excitation/inhibition and the activation of microglia using mouse organotypic entorhino-hippocampal tissue cultures. We found that low concentrations of TNF enhanced excitatory synaptic strength while not affecting inhibitory neurotransmission. At higher concentrations, TNF increased inhibitory neurotransmission without affecting excitatory synaptic strength. Both low and high concentrations of TNF induced the synaptic accumulation of GluA1-containing AMPA receptors, suggesting that a high concentration of TNF exerts a homeostatic effect on excitatory neurotransmission that prevents synaptic strengthening. Consistent with this, high, but not low, concentrations of TNF activated microglia. Moreover, high concentrations of TNF enhanced excitatory neurotransmission in microglia-depleted tissue cultures. These findings extend our knowledge on the role of TNF on synaptic plasticity by demonstrating concentration-dependent effects on excitatory and inhibitory neurotransmission. They reveal a TNF-mediated negative feedback mechanism on excitatory neurotransmission that is dependent on the activation of microglia, thereby emphasizing their role as gatekeepers of TNF-mediated plasticity and homeostasis.