title: Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.
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.
authors.affiliation: 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.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Schoenfeld
authors.affiliation: 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.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Bell
authors.affiliation: McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hinchey
authors.affiliation: Bolduc Laboratory, Department of Pediatrics, Center for Neuroscience, University of Alberta Edmonton, AB, Canada.
authors.forename: Cory
authors.initials: C
authors.lastname: Rosenfelt
authors.affiliation: Zukin Laboratory, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gertner
authors.affiliation: McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Campbell
authors.affiliation: Jongens Laboratory, Department of Genetics, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Emerson
authors.affiliation: McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hinchey
authors.affiliation: McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kollaros
authors.affiliation: 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.
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Ferrick
authors.affiliation: Bolduc Laboratory, Department of Pediatrics, Center for Neuroscience, University of Alberta Edmonton, AB, Canada.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Chambers
authors.affiliation: Bolduc Laboratory, Department of Pediatrics, Center for Neuroscience, University of Alberta Edmonton, AB, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Langer
authors.affiliation: Siegel Laboratory, Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Sust
authors.affiliation: Jongens Laboratory, Department of Genetics, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
authors.forename: Aatika
authors.initials: A
authors.lastname: Malik
authors.affiliation: McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Terlizzi
authors.affiliation: McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Liebelt
authors.affiliation: McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ferreiro
authors.affiliation: Zukin Laboratory, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Sharma
authors.affiliation: McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Koenigsberg
authors.affiliation: McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Choi
authors.affiliation: Arnold Laboratory, Department of Psychiatry, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Louneva
authors.affiliation: Arnold Laboratory, Department of Psychiatry, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.affiliation: Siegel Laboratory, Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Featherstone
authors.affiliation: Siegel Laboratory, Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Siegel
authors.affiliation: Zukin Laboratory, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: R Suzanne
authors.initials: RS
authors.lastname: Zukin
authors.affiliation: McDonald Laboratory, Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University Bronx, NY, USA.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: McDonald
authors.affiliation: Bolduc Laboratory, Department of Pediatrics, Center for Neuroscience, University of Alberta Edmonton, AB, Canada.
authors.forename: Francois V
authors.initials: FV
authors.lastname: Bolduc
authors.affiliation: Jongens Laboratory, Department of Genetics, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Jongens
authors.affiliation: 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.
authors.forename: Sean M J
authors.initials: SM
authors.lastname: McBride
keywords: Fragile X; GSK-3β; PDE-4; group II mGluR; lithium; mTOR; tau