Multiple drug treatments thatincrease cAMP signaling restorelong-term memory and aberrantsignaling in fragile X syndromemodels

Catherine H. Choi, Brian P. Schoenfeld, Aaron J. Bell, Joseph Hinchey, Cory Rosenfelt, Michael J. Gertner, Sean R. Campbell, Danielle Emerson, Paul Hinchey, Maria Kollaros, Neal J. Ferrick, Daniel B. Chambers, Steven Langer, Steven Sust, Aatika Malik, Allison M. Terlizzi, David A. Liebelt, David Ferreiro, Ali Sharma, Eric KoenigsbergRichard J. Choi, Natalia Louneva, Steven E. Arnold, Robert E. Featherstone, Steven J. Siegel, R. Suzanne Zukin, Thomas V. McDonald, Francois V. Bolduc, Thomas A. Jongens, Sean M.J. McBride

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Article number136
JournalFrontiers in Behavioral Neuroscience
Volume10
Issue numberJun
DOIs
StatePublished - Jun 30 2016

Keywords

  • Fragile X
  • GSK-3β
  • Group II mGluR
  • Lithium
  • MTOR
  • PDE-4
  • Tau

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

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    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., ... McBride, S. M. J. (2016). Multiple drug treatments thatincrease cAMP signaling restorelong-term memory and aberrantsignaling in fragile X syndromemodels. Frontiers in Behavioral Neuroscience, 10(Jun), [136]. https://doi.org/10.3389/fnbeh.2016.00136