Metaplasticity within the spinal cord: Evidence brain-derived neurotrophic factor (BDNF), tumor necrosis factor (TNF), and alterations in GABA function (ionic plasticity) modulate pain and the capacity to learn

Neurobiol Learn Mem. 2018 Oct:154:121-135. doi: 10.1016/j.nlm.2018.04.007. Epub 2018 Apr 7.


Evidence is reviewed that behavioral training and neural injury can engage metaplastic processes that regulate adaptive potential. This issue is explored within a model system that examines how training affects the capacity to learn within the lower (lumbosacral) spinal cord. Response-contingent (controllable) stimulation applied caudal to a spinal transection induces a behavioral modification indicative of learning. This behavioral change is not observed in animals that receive stimulation in an uncontrollable manner. Exposure to uncontrollable stimulation also engages a process that disables spinal learning for 24-48 h. Controllable stimulation has the opposite effect; it engages a process that enables learning and prevents/reverses the learning deficit induced by uncontrollable stimulation. These observations suggest that a learning episode can impact the capacity to learn in future situations, providing an example of behavioral metaplasticity. The protective/restorative effect of controllable stimulation has been linked to an up-regulation of brain-derived neurotrophic factor (BDNF). The disruption of learning has been linked to the sensitization of pain (nociceptive) circuits, which is enabled by a reduction in GABA-dependent inhibition. After spinal cord injury (SCI), the co-transporter (KCC2) that regulates the outward flow of Cl- is down-regulated. This causes the intracellular concentration of Cl- to increase, reducing (and potentially reversing) the inward flow of Cl- through the GABA-A receptor. The shift in GABA function (ionic plasticity) increases neural excitability caudal to injury and sets the stage for nociceptive sensitization. The injury-induced shift in KCC2 is related to the loss of descending serotonergic (5HT) fibers that regulate plasticity within the spinal cord dorsal horn through the 5HT-1A receptor. Evidence is presented that these alterations in spinal plasticity impact pain in a brain-dependent task (place conditioning). The findings suggest that ionic plasticity can affect learning potential, shifting a neural circuit from dampened/hard-wired to excitable/plastic.

Keywords: BDNF; Central sensitization; Instrumental conditioning; KCC2; Spinal cord injury; TNF.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / physiology*
  • Humans
  • Learning / physiology*
  • Models, Neurological
  • Neuronal Plasticity*
  • Neurons / physiology
  • Nociception / physiology
  • Pain / physiopathology*
  • Spinal Cord / physiology*
  • Tumor Necrosis Factor-alpha / physiology*
  • gamma-Aminobutyric Acid / physiology*


  • Brain-Derived Neurotrophic Factor
  • Tumor Necrosis Factor-alpha
  • gamma-Aminobutyric Acid