Glial Tumor Necrosis Factor Alpha (TNFα) Generates Metaplastic Inhibition of Spinal Learning

Abstract

Injury-induced overexpression of tumor necrosis factor alpha (TNFα) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNFα 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 TNFα. We found that intermittent stimulation increased protein levels in the spinal cord. Using intrathecal pharmacological manipulations, we showed TNFα 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 TNFα and involved downstream alterations in calcium-permeable AMPA receptors. These findings suggest a crucial role for glial TNFα in undermining spinal learning, and demonstrate the therapeutic potential of inhibiting TNFα activity to rescue and restore adaptive spinal plasticity to the injured spinal cord. TNFα modulation represents a novel therapeutic target for improving rehabilitation after spinal cord injury.

What Is Being Trained? How Divergent Forms of Plasticity Compete To Shape Locomotor Recovery after Spinal Cord Injury

“…[124][125][126][127] Several groups have subsequently demonstrated the existence of metaplasticity in spinal cord locomotor circuitry below SCI. [128][129][130][131][132] Understanding spinal cord (re)-training potential as a form of metaplasticity provides a fertile literature to draw from for pharmacological targets to carefully tune and improve spinal cord training after injury.…”

Stretching adversely modulates locomotor capacity following spinal cord injury via activation of nociceptive afferents.

“…Since AMPA receptors GluA2 subunits are essentially calcium ionophores their upregulation further increases intracellular calcium initiating a positive feedback loop that leads to an altered cellular function. [213,298]. Nociceptive signaling also activates glial cells which have been shown to mediate long term potentiation (LTP)…”

“…The glial cell products and mediators of these effects include nitric oxide, prostaglandins, cytokines IL-1b and IL-6 as well as tumor necrosis factor alpha (TNFα) [300]. Huie et al, have shown that TNFα plays a critical role in the induction of spinal learning deficits [298] likely through the mechanisms involving AMPA receptor trafficking as has been demonstrated by others [301]. In addition Grau et al, has investigated the role of endogenous opioids in the mediation of spinal learning deficits as a result of uncontrollable nociceptive stimulation.…”

Gain and loss of functional locomotor recovery following contusive spinal cord injury in the adult rat.

“…Sensitization resulting from noxious afferent input is SP dependent (Ferguson et aL, 2006), and excessive stimulation by SP has been shown, in a series of two papers by Baumbauer and colleagues (2007b, a), to diminish plasticity by creating a learning deficit in a model of spinal instrumental learning after transection. Noxious afferent input can also disrupt spinal learning via TNFa activation (Huie et aL, 2012) a key pro-inflammatory cytokine and mechanism of immune-mediated central conduction failure after SCI mentioned above (Davies et aL, 2006;Hayes et aL, 2007). TNFa exerts a decrease, almost extinction, in compound action potential amplitude, depolarization of resting potential in a dose dependent and reversible manner (Davies et aL, 2006).…”

“…TNFa exerts a decrease, almost extinction, in compound action potential amplitude, depolarization of resting potential in a dose dependent and reversible manner (Davies et aL, 2006). Furthermore, spinal learning deficit is reversed when TNFa was inhibited (Huie et aL, 2012). In essence, spared spinal cord tissue after contusion injury is highly sensitive to peripheral inflammation and pain such that regaining proper neuron firing and conduction is repeatedly interrupted by factors contributing to a state of spinal shock and delayed from functional reorganization.…”