Tumor Necrosis Factor-α Signaling Maintains the Ability of Cortical Synapses to Express Synaptic Scaling

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