Tumor necrosis factor (TNF) modulates synaptic plasticity in a concentration-dependent manner through intracellular calcium stores.

The role of inflammatory signaling pathways in synaptic plasticity has long been identified. Yet, it remains unclear how inflammatory cytokines assert their pleiotropic effects on neural plasticity. Moreover, the neuronal targets through which inflammatory cytokines assert their effects on plasticity remain not well-understood. In an attempt to learn more about the plasticity-modulating effects of the pro-inflammatory cytokine tumor necrosis factor (TNF), we used two-pathway long-term potentiation (LTP) experiments at Schaffer collateral-CA1 synapses to test for concentration-dependent effects of TNF on synaptic plasticity. We report that high concentrations of TNF (1 μg/mL) impair the ability of mouse CA1 pyramidal neurons to express synaptic plasticity without affecting baseline synaptic transmission and/or previously established LTP. Interestingly, 100 ng/mL of TNF has no apparent effect on LTP, while low concentrations (1 ng/mL) promote the ability of neurons to express LTP. These dose-dependent metaplastic effects of TNF are modulated by intracellular calcium stores: Pharmacological activation of intracellular calcium stores with ryanodine (10 μM) reverses the negative effects of TNF[high], and the plasticity-promoting effects of TNF[low] are blocked when intracellular calcium stores are depleted with thapsigargin (1 μM). Consistent with this result, TNF does not promote plasticity in synaptopodin-deficient preparations, which show deficits in neuronal calcium store-mediated synaptic plasticity. Thus, we propose that TNF mediates its pleiotropic effects on synaptic plasticity in a concentration-dependent manner through signaling pathways that are modulated by intracellular calcium stores and require the presence of synaptopodin. These results demonstrate that TNF can act as mediator of metaplasticity, which is of considerable relevance in the context of brain diseases associated with increased TNF levels and alterations in synaptic plasticity. KEY MESSAGES: • TNF modulates the ability of neurons to express synaptic plasticity. • High concentrations of TNF impair synaptic plasticity. • Low concentrations of TNF improve synaptic plasticity. • TNF does not affect previously established long-term potentiation. • Plasticity effects of TNF are modulated by intracellular calcium stores.