Injury-induced overexpression of tumor necrosis factor alpha (TNF) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNF might also act to upset spinal function by modulating spinal plasticity. Using a model of instrumental learning in the injured spinal cord, we have previously shown that peripheral intermittent stimulation can produce a plastic change in spinal plasticity (metaplasticity), resulting in the prolonged inhibition of spinal learning. We hypothesized that spinal metaplasticity may be mediated by TNF. We found that intermittent stimulation increased protein levels in the spinal cord. Using intrathecal pharmacological manipulations, we showed TNF to be both necessary and sufficient for the long-term inhibition of a spinal instrumental learning task. These effects were found to be dependent on glial production of TNF and involved downstream alterations in calcium-permeable AMPA receptors. These findings suggest a crucial role for glial TNF in undermining spinal learning, and demonstrate the therapeutic potential of inhibiting TNF activity to rescue and restore adaptive spinal plasticity to the injured spinal cord. TNF modulation represents a novel therapeutic target for improving rehabilitation after spinal cord injury.
