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Excessive ERK-dependent synaptic clustering drives enhanced motor learning in the MECP2 duplication syndrome mouse model of autism

Ryan Thomas Ash, Shelly Alexandra Buffington, Jiyoung Park, Mauro Costa-Mattioli, Huda Yaya Zoghbi, Stelios Manolis Smirnakis
doi: https://doi.org/10.1101/100875
Ryan Thomas Ash
1Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030
2Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030
3Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston MA 021150
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Shelly Alexandra Buffington
4Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030
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Jiyoung Park
1Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030
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Mauro Costa-Mattioli
1Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030
4Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030
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Huda Yaya Zoghbi
1Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030
5Department of Pediatrics, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX 77030
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030
7Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
8Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030
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Stelios Manolis Smirnakis
1Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030
3Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston MA 021150
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  • For correspondence: SMSMIRNAKIS@partners.org
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Abstract

Autism-associated genetic mutations may produce altered learning abilities by perturbing the balance between stability and plasticity of synaptic connections in the brain. Here we report an increase in the stabilization of dendritic spines formed during repetitive motor learning in the mouse model of MECP2-duplication syndrome, a high-penetrance form of syndromic autism. This increased stabilization is mediated entirely by spines that form cooperatively in clusters. The number of clusters formed and stabilized predicts the mutant’s enhanced motor learning and memory phenotype, reminiscent of savant-like behaviors occasionally associated with autism.

The ERK signaling pathway, which promotes cooperative plasticity between spines, was found to be hyperactive in MECP2-duplication motor cortex specifically after training. Inhibition of ERK signaling normalizes clustered spine stabilization and rescues motor learning behavior in mutants. We conclude that learning-associated dendritic spine clustering stabilized by hyperactive ERK signaling drives abnormal motor learning and memory consolidation in this model of syndromic autism.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 16, 2017.
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Excessive ERK-dependent synaptic clustering drives enhanced motor learning in the MECP2 duplication syndrome mouse model of autism
Ryan Thomas Ash, Shelly Alexandra Buffington, Jiyoung Park, Mauro Costa-Mattioli, Huda Yaya Zoghbi, Stelios Manolis Smirnakis
bioRxiv 100875; doi: https://doi.org/10.1101/100875
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Excessive ERK-dependent synaptic clustering drives enhanced motor learning in the MECP2 duplication syndrome mouse model of autism
Ryan Thomas Ash, Shelly Alexandra Buffington, Jiyoung Park, Mauro Costa-Mattioli, Huda Yaya Zoghbi, Stelios Manolis Smirnakis
bioRxiv 100875; doi: https://doi.org/10.1101/100875

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