Group I Metabotropic Glutamate Receptors Control Metaplasticity of Spinal Cord Learning through a Protein Kinase C-Dependent Mechanism

Abstract

Neurons within the spinal cord can support several forms of plasticity, including response-outcome (instrumental) learning. After a complete spinal transection, experimental subjects are capable of learning to hold the hindlimb in a flexed position (response) if shock (outcome) is delivered to the tibialis anterior muscle when the limb is extended. This response-contingent shock produces a robust learning that is mediated by ionotropic glutamate receptors (iGluRs). Exposure to nociceptive stimuli that are independent of limb position (e.g., uncontrollable shock; peripheral inflammation) produces a long-term (Ͼ24 h) inhibition of spinal learning. This inhibition of plasticity in spinal learning is itself a form of plasticity that requires iGluR activation and protein synthesis. Plasticity of plasticity (metaplasticity) in the CNS has been linked to group I metabotropic glutamate receptors (subtypes mGluR1 and mGluR5) and activation of protein kinase C (PKC). The present study explores the role of mGluRs and PKC in the metaplastic inhibition of spinal cord learning using a combination of behavioral, pharmacological, and biochemical techniques. Activation of group I mGluRs was found to be both necessary and sufficient for metaplastic inhibition of spinal learning. PKC was activated by stimuli that inhibit spinal learning, and inhibiting PKC activity restored the capacity for spinal learning. Finally, a PKC inhibitor blocked the metaplastic inhibition of spinal learning produced by a group I mGluR agonist. The data strongly suggest that group I mGluRs control metaplasticity of spinal learning through a PKC-dependent mechanism, providing a potential therapeutic target for promoting use-dependent plasticity after spinal cord injury.

The association between spinal cord trauma-sensitive miRNAs and pain sensitivity, and their regulation by morphine

“…Following surgery, the wound was closed with Michel clips. T12 level contusion models have been routinely used by members of our group to define spinal cord learning circuits and molecular mechanisms involved with recovery of function (Brown et al, 2011; Ferguson et al, 2008; Hook et al, 2011). Lesions at this level result in well-defined and replicable sensory-motor deficits, and we therefore chose to utilize contusion at this level to also examine changes in miRNA expression.…”

Temporal regularity determines the impact of electrical stimulation on tactile reactivity and response to capsaicin in spinally transected rats

“…For subjects in the fixed spaced condition, shocks occurred at regular (2-s) intervals. Variable stimulation was created using a rectangular distribution that varied between 0.2 and 3.8 s, with a mean interstimulus interval (ISI) of 2 s. Prior work has shown that variable shock undermines learning (Crown et al, 2002; Baumbauer et al, 2007; Baumbauer et al, 2008; Ferguson et al, 2008; Baumbauer et al, 2009), while fixed shock does not (Baumbauer et al, 2008; Baumbauer et al, 2009). …”

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.…”