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Front Behav Neurosci. 2016 Jun 30;10:136. doi: 10.3389/fnbeh.2016.00136. eCollection 2016.

Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

Author information

1
McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva UniversityBronx, NY, USA; Department of Dermatology, Dermatology Clinic, Drexel University College of MedicinePhiladelphia, PA, USA; Jongens Laboratory, Department of Genetics, University of Pennsylvania School of MedicinePhiladelphia, PA, USA.
2
McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva UniversityBronx, NY, USA; Jongens Laboratory, Department of Genetics, University of Pennsylvania School of MedicinePhiladelphia, PA, USA.
3
McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
4
Bolduc Laboratory, Department of Pediatrics, Center for Neuroscience, University of Alberta Edmonton, AB, Canada.
5
Zukin Laboratory, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
6
Jongens Laboratory, Department of Genetics, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
7
Siegel Laboratory, Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
8
Arnold Laboratory, Department of Psychiatry, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
9
McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva UniversityBronx, NY, USA; Jongens Laboratory, Department of Genetics, University of Pennsylvania School of MedicinePhiladelphia, PA, USA; Siegel Laboratory, Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania School of MedicinePhiladelphia, PA, USA.

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.

KEYWORDS:

Fragile X; GSK-3β; PDE-4; group II mGluR; lithium; mTOR; tau

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