p38 MAP Kinase Mediates Both Short-Term and Long-Term Synaptic Depression in Aplysia

• Published in: The Journal of neuroscience Vol. 23; no. 19; pp. 7317 - 7325
• Main Authors: Guan, Zhonghui, Kim, Joung-Hun, Lomvardas, Stavros, Holick, Kerri, Xu, Shiqin, Kandel, Eric R, Schwartz, James H
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 13.08.2003; Society for Neuroscience
• Subjects: Activating Transcription Factor 2; Animals; Aplysia; Arachidonic Acid - metabolism; Cells, Cultured; Cellular/Molecular; Cyclic AMP Response Element-Binding Protein - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - physiology; Enzyme Inhibitors - pharmacology; FMRFamide - pharmacology; Histone Deacetylases - metabolism; Long-Term Synaptic Depression - drug effects; MAP Kinase Signaling System; Marine; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - physiology; Models, Biological; Nerve Tissue Proteins - metabolism; Neuronal Plasticity - drug effects; Neurons - drug effects; Neurons - enzymology; p38 Mitogen-Activated Protein Kinases; Phospholipases A - metabolism; Phospholipases A2; Phosphorylation; Repressor Proteins - metabolism; Serotonin - pharmacology; Transcription Factors - antagonists & inhibitors
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.23-19-07317.2003

At Aplysia sensory-to-motor neuron synapses, the inhibitory neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFa) produces depression, and serotonin (5-HT) produces facilitation. Short-term depression has been found to result from the activation of a phospholipase A2. The released arachidonate is metabolized by 12-lipoxygenase to active second messengers. We find that FMRFa leads to the phosphorylation and activation of p38 mitogen-activated protein (MAP) kinase. Short-term depression and the release of arachidonate are blocked by the specific p38 kinase inhibitor SB 203580. Both the inhibitor and an affinity-purified antibody raised against recombinant Aplysia p38 kinase injected into sensory neurons prevented long-term depression, which depends on the phosphorylation of translation factors cAMP response element-binding protein 2 (CREB2) and activating transcription factor 2. Facilitation produced by 5-HT, on the other hand, inactivates p38 kinase. Chromatin immunoprecipitation assays indicate that p38 kinase activates CREB2. p38 kinase also is pivotal in the bidirectional regulation of synaptic plasticity: when the kinase is inhibited, brief treatment with 5-HT that normally produces only short-term facilitation now results in long-term facilitation. Conversely, in sensory neurons injected with the activated kinase, long-term facilitation is blocked, and brief exposure to FMRFa, which normally results in short-term depression, results in long-term depression. We conclude that p38 kinase, which itself is bidirectionally regulated by FMRFa and 5-HT, acts as a modulator of synaptic plasticity by positively regulating depression and serving as an inhibitory constraint for facilitation.