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

Autor:	Choi CH; 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., Schoenfeld BP; 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., Weisz ED; Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104., Bell AJ; 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., Chambers DB; Department of Pediatrics, Center for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2N8, Canada., Hinchey J; Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461., Choi RJ; Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461., Hinchey P; Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461., Kollaros M; Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461., Gertner MJ; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461., Ferrick NJ; 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., Terlizzi AM; Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461., Yohn N; Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104., Koenigsberg E; Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461., Liebelt DA; Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461., Zukin RS; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461., Woo NH; Division of Anesthesia, Analgesia and Addiction Products, Office of Drug Evaluation II, OND/CDER/FDA, Silver Spring, Maryland 20993., Tranfaglia MR; FRAXA Research Foundation, Newburyport, Massachusetts 01950, and., Louneva N; Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104., Arnold SE; Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104., Siegel SJ; Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104., Bolduc FV; 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., McDonald TV; 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., Jongens TA; 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., McBride SM; 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.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2015 Jan 07; Vol. 35 (1), pp. 396-408.
DOI:	10.1523/JNEUROSCI.1356-12.2015
Abstrakt:	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. (Copyright © 2015 the authors 0270-6474/15/350396-13$15.00/0.)
Databáze:	MEDLINE
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