Abstract
Extracellular signal-regulated kinases (ERK1 and 2) are synaptic signaling components necessary for several forms of learning. In mice lacking ERK1, we observe a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens. At the cellular level, we find that ablation of ERK1 results in a stimulus-dependent increase of ERK2 signaling, likely due to its enhanced interaction with the upstream kinase MEK. Consistently, such activity change is responsible for the hypersensitivity of ERK1 mutant mice to the rewarding properties of morphine. Our results reveal an unexpected complexity of ERK-dependent signaling in the brain and a critical regulatory role for ERK1 in the long-term adaptive changes underlying striatum-dependent behavioral plasticity and drug addiction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amygdala / cytology
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Amygdala / enzymology
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Animals
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Avoidance Learning / physiology
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Cognition Disorders / enzymology
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Cognition Disorders / genetics
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Cognition Disorders / pathology
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Corpus Striatum / abnormalities
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Corpus Striatum / cytology
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Corpus Striatum / enzymology*
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Female
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Hippocampus / cytology
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Hippocampus / enzymology
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Long-Term Potentiation / genetics*
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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Male
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Memory / physiology*
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / deficiency*
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Mitogen-Activated Protein Kinases / genetics
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Morphine / pharmacology
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Motor Activity / genetics
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Mutation / genetics
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Nerve Net / abnormalities
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Nerve Net / cytology
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Nerve Net / enzymology
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Nervous System Malformations / enzymology
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Nervous System Malformations / genetics
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Nervous System Malformations / pathology
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Nucleus Accumbens / abnormalities
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Nucleus Accumbens / cytology
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Nucleus Accumbens / enzymology*
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Presynaptic Terminals / enzymology*
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Presynaptic Terminals / ultrastructure
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Synaptic Transmission / genetics*
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Up-Regulation / genetics
Substances
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Morphine
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases