Cited by 46Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchNeurobiology and Insect Physiology Research

Multiple drug treatments that increase cAMP signaling restore long-term memory and aberrant signaling in fragile X syndrome models

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Choi, Catherine H., Schoenfeld, Brian P., Bell, Aaron J., Hinchey, Joseph, Rosenfelt, Cory, Gertner, Michael J., Campbell, Sean R., Emerson, Danielle +22 more·2016·Frontiers in Behavioral Neuroscience

Abstract

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.

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  • Animal studies have shown that a phosphordiasterase 4DE inhibitor can rescue features of FXS in the KO mouse model and Drosophila model and can raise cAMP levels to normal.

    “Recent animal studies have shown that an inhibitor of cAMP breakdown called a phosphordiasterase 4DE inhibitor can rescue features of FXS in the KO mouse model and Drosophila model and can raise the cAMP levels to normal [141, 142].”

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Authors
Choi, C. H., Schoenfeld, B. P., Bell, A. J., Hinchey, J., Rosenfelt, C., Gertner, M. J., Campbell, S. R., Emerson, D., Hinchey, P., Kollaros, M., Ferrick, N. J., Chambers, D. B., Langer, S., Sust, S., Malik, A., Terlizzi, A. M., Liebelt, D. A., Ferreiro, D., Sharma, A., Koenigsberg, E., Choi, R. J., Louneva, N., Arnold, S. E., Featherstone, R. E., Siegel, S. J., Zukin, R. S., McDonald, T. V., Bolduc, F. V., Jongens, T. A., & McBride, S. M. J.
Affiliations
  • Albert Einstein College of Medicine (US)
  • University of Alberta (CA)
  • University of Pennsylvania (US)
Corresponding author
  • McDonald, Thomas V.
  • Jongens, Thomas A.
  • McBride, Sean M. J.
Venue
Frontiers in Behavioral Neuroscience
Published
2016-06-30
Volume
10
Pages
136-136
ISSN
1662-5153 (ISSN-L)
OpenAlex
W2465376623
Cited by
46
References
152
Citations by year
2026: 1 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 6 · 2017: 3 · 2016: 1
FWCI
4.30
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Behavioral Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense (AR1101189)
  • Autism Speaks
  • FRAXA Research Foundation (AR1101189)
  • University of Pennsylvania
  • Yeshiva University
  • Drexel University
  • National Fragile X Foundation
  • Canadian Child Health Clinician Scientist Program
  • National Institutes of Health
  • Albert Einstein College of Medicine, Yeshiva University
  • National Institute of Mental Health (R25MH060490, R01MH092877)
  • National Institute of General Medical Sciences (R01GM086902)
  • National Institute of Neurological Disorders and Stroke (R01NS045693)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
Keywords
fragile X syndrome, cAMP signaling, long-term memory, FMRP, lithium, phosphodiesterase-4 inhibitors, mGluR antagonists, DHPG, long-term depression, hippocampus, Drosophila model, mouse model, intellectual disability, autism spectrum disorder

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