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J Neurosci. 2015 Jan 7;35(1):396-408. doi: 10.1523/JNEUROSCI.1356-12.2015.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Author information

1
Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, Department of Medicine, Lehigh Valley Health System, Allentown, Pennsylvania 18103, Department of Dermatology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19107.
2
Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
3
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
4
Department of Pediatrics, Center for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2N8, Canada.
5
Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
6
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461.
7
Division of Anesthesia, Analgesia and Addiction Products, Office of Drug Evaluation II, OND/CDER/FDA, Silver Spring, Maryland 20993.
8
FRAXA Research Foundation, Newburyport, Massachusetts 01950, and.
9
Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
10
Department of Pediatrics, Center for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2N8, Canada, tom.mcdonald@einstein.yu.edu fbolduc@ualberta.ca smjmcbride@gmail.com jongens@mail.med.upenn.edu.
11
Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, tom.mcdonald@einstein.yu.edu fbolduc@ualberta.ca smjmcbride@gmail.com jongens@mail.med.upenn.edu.
12
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, tom.mcdonald@einstein.yu.edu fbolduc@ualberta.ca smjmcbride@gmail.com jongens@mail.med.upenn.edu.
13
Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 tom.mcdonald@einstein.yu.edu fbolduc@ualberta.ca smjmcbride@gmail.com jongens@mail.med.upenn.edu.

Abstract

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

KEYWORDS:

Drosophila; cAMP; fragile X; memory; mouse; phosphodiesterase 4

PMID:
25568131
PMCID:
PMC4287155
DOI:
10.1523/JNEUROSCI.1356-12.2015
[Indexed for MEDLINE]
Free PMC Article

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