Pharmacological Rescue of Synaptic Plasticity, Courtship Behavior, and Mushroom Body Defects in a Drosophila Model of Fragile X Syndrome

Sean M.J. McBride, Catherine H. Choi, Yan Wang, David Liebelt, Evan Braunstein, David Ferreiro, Amita Sehgal, Kathleen K. Siwicki, Thomas C. Dockendorff, Hanh T. Nguyen, Thomas V. McDonald and Thomas A. Jongens

Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Medical Scientist Training Program, Albert Einstein College of Medicine, Bronx, New York 10461, USA
Section of Molecular Cardiology, Departments of Medicine and Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
MD-PhD Program, Departments of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Howard Hughes Medical Institute and Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Department of Biology, Swarthmore College, Swarthmore, Pennsylvania 19081, USA
Department of Zoology, Miami University, Oxford, Ohio 45056 USA.

Fragile X syndrome is a leading heritable cause of mental retardation that results from the loss of FMR1 gene function. A Drosophila model for Fragile X syndrome, based on the loss of dfmr1 activity, exhibits phenotypes that bear similarity to Fragile X-related symptoms. Herein, we demonstrate that treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium can rescue courtship and mushroom body defects observed in these flies. Furthermore, we demonstrate that dfmr1 mutants display cognitive deficits in experience-dependent modification of courtship behavior, and treatment with mGluR antagonists or lithium restores these memory defects. These findings implicate enhanced mGluR signaling as the underlying cause of the cognitive, as well as some of the behavioral and neuronal, phenotypes observed in the Drosophila Fragile X model. They also raise the possibility that compounds having similar effects on metabotropic glutamate receptors may ameliorate cognitive and behavioral defects observed in Fragile X patients.