Cocaine Regulates MEF2 to Control Synaptic and Behavioral Plasticity
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Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine.
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MEF2 controls a gene expression program that has a role in developmental synapse elimination.
“The transcription factor MEF2 controls a program of gene expression that has a role in developmental synapse elimination26,29,65,66.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [66]
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Self-citation
- Authors
- Pulipparacharuvil, S., Renthal, W., Hale, C. F., Taniguchi, M., Xiao, G., Kumar, A., Russo, S. J., Sikder, D., Dewey, C. M., Davis, M. M., Greengard, P., Nairn, A. C., Nestler, E. J., & Cowan, C. W.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Yale University (US)
- Rockefeller University (US)
- Corresponding author
- Cowan, Christopher W.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 59
- Issue
- 4
- Pages
- 621-633
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2626175
- OpenAlex
- W2047660382
- Cited by
- 281
- References
- 42
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 14 · 2023: 4 · 2022: 16 · 2021: 11 · 2020: 7 · 2019: 11 · 2018: 7 · 2017: 16 · 2016: 11 · 2015: 19 · 2014: 14 · 2013: 25 · 2012: 38
- FWCI
- 10.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Whitehall Foundation
- National Institute of Mental Health (P50MH074866)
- National Institute on Drug Abuse (P01DA010044, P01DA008227, R01DA007359)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- cocaine, MEF2 transcription factors, nucleus accumbens, dendritic spines, synaptic plasticity, behavioral sensitization, cAMP signaling, calmodulin signaling, calcineurin, striatum
- MeSH terms
- Adaptation, Physiological, Cyclic AMP, Animals, Behavior, Animal, Cells, Cultured, Cocaine, Drug Administration Schedule, Male, Mice, Inbred C57BL, Neuronal Plasticity, Neurons, Nucleus Accumbens, Synapses, Down-Regulation, Neostriatum, Rats, Sprague-Dawley, Myogenic Regulatory Factors, Dopamine Uptake Inhibitors, Cyclin-Dependent Kinases, Rats, Long-Evans, Gene Expression Profiling, Dendritic Spines, Mice, Rats, MEF2 Transcription Factors
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