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The Journal of Neuroscience, November 12, 2008, 28(46):11939-11949; doi:10.1523/JNEUROSCI.3098-08.2008
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Development/Plasticity/Repair
Group I Metabotropic Glutamate Receptors Control Metaplasticity of Spinal Cord Learning through a Protein Kinase C-Dependent Mechanism
Adam R. Ferguson,1 * Kevin A. Bolding,2 * J. Russell Huie,3 Michelle A. Hook,3 Daniel R. Santillano,4 Rajesh C. Miranda,4 andJames W. Grau3 1Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94110, 2State University of New York Downstate Medical Center, Brooklyn, New York 11203, 3Department of Psychology, Texas A&M University, and 4Department of Anatomy and Neurobiology, Texas A&M University Health Science Center, College Station, Texas 77843
Correspondence should be addressed to Adam R. Ferguson, Brain and Spinal Injury Center, University of California, San Francisco, 1001 Potrero Avenue, Building 1, Room 101, San Francisco, CA 94110. Email: adam.ferguson{at}ucsf.edu
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 (>24 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.
Key words: spinal cord injury; spinal learning; use-dependent plasticity; nociception; NMDA; AMPA
Received July 3, 2008; revised Sept. 3, 2008; accepted Oct. 2, 2008.
Correspondence should be addressed to Adam R. Ferguson, Brain and Spinal Injury Center, University of California, San Francisco, 1001 Potrero Avenue, Building 1, Room 101, San Francisco, CA 94110. Email: adam.ferguson{at}ucsf.edu
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[Abstract] [Full Text] [PDF]
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