Tumor necrosis factor-α signaling maintains the ability of cortical synapses to express synaptic scaling

Glial tumor necrosis factor-α (TNFα) is essential for scaling up of synapses during prolonged activity blockade, but whether TNFα is an instructive or permissive signal is not known. Here we show in rat cortical neurons that the effects of TNFα and activity blockade are not additive; whereas TNFα increased AMPA quantal amplitude at control synapses, TNFα reduced quantal amplitude at prescaled synapses, demonstrating state-dependent effects of TNFα signaling on the scaling process. Whereas synaptic scaling during prolonged activity blockade [24 h tetrodotoxin (TTX)] was prevented by blocking TNFα signaling, early scaling (6 h TTX) was not, unless TNFα signaling was first blocked for 24 h. Moreover, when synapses were prescaled, prolonged (24 h) but not brief (6 h) blockade of TNFα signaling reversed scaling. Finally, prolonged block of TNFα signaling modified the synaptic localization of several scaffold proteins, suggesting that maintenance of postsynaptic density composition is TNFα dependent. Together, these data suggest that TNFα is not an instructive signal for scaling but rather is critical for maintaining synapses in a plastic state in which synaptic scaling can be expressed.