Fragile X syndrome is one of the most commonly inherited forms of mental retardation and is caused by the loss of FMR1 gene function. Patients with fragile X syndrome suffer from a variety of symptoms including;mental retardation, attention deficit, hyperactivity, sleep disorders, anxiety, unstable mood and autistic-like behaviors. In previous studies, we have characterized a Drosophila model for Fragile X, based on dfmr1 loss of function mutations. Surprisingly, dfmr1 mutants display several phenotypes that bear similarity to Fragile X symptoms. These phenotypes include courtship defects, memory deficits, lack of proper circadian regulation and neuroanatomical defects. Recent observations have indicated that enhanced metabotropic glutamate receptor (mGluR) signaling is a cause of a large number of the Fragile X symptoms. In support of this model, we previously demonstrated that treatment with mGluR antagonists rescues several of the dfmr1 mutant phenotypes, including the courtship defects, memory and some neuroanatomical defects. We now are poised to examine the biological relevance of a reported deficit in cAMP regulation. We will also map the requirements of dfmr1 in the brain for normal circadian behavior. In another study we have been investigating the mechanism by which dFMR1 functions with a key member of the small RNA pathways to regulate circadian behavior. These studies will impact our basic understanding of the primary defects that lead to fragile X, as well a improve our general knowledge of the processes of cognition and circadian behavior.

Public Health Relevance

This proposal investigates a Drosophila model for Fragile X Syndrome at multiple levels, including examination of defects in physiology and neuronal circuits that cause relevant phenotypes in memory and circadian behavior. Findings from this research will both increase our understanding of the underlying defects that cause fragile X as well as increase our basic knowledge on the requirements for proper cognition and circadian behavior, as well as how the small RNA pathway is linked to the FMR1.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Krasnewich, Donna M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Monyak, R E; Emerson, D; Schoenfeld, B P et al. (2017) Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model. Mol Psychiatry 22:1140-1148
Choi, Catherine H; Schoenfeld, Brian P; Bell, Aaron J et al. (2016) Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models. Front Behav Neurosci 10:136
Choi, Catherine H; Schoenfeld, Brian P; Weisz, Eliana D et al. (2015) PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome. J Neurosci 35:396-408
Wolman, Marc A; de Groh, Eric D; McBride, Sean M et al. (2014) Modulation of cAMP and ras signaling pathways improves distinct behavioral deficits in a zebrafish model of neurofibromatosis type 1. Cell Rep 8:1265-70
Schoenfeld, Brian P; Choi, Richard J; Choi, Catherine H et al. (2013) The Drosophila DmGluRA is required for social interaction and memory. Front Pharmacol 4:64
McBride, Sean M; Holloway, Sandra L; Jongens, Thomas A (2012) Using Drosophila as a tool to identify Pharmacological Therapies for Fragile X Syndrome. Drug Discov Today Technol 10:e129-e136
Pepper, Anita; Bhogal, Balpreet; Jongens, Thomas (2012) Tandem Affinity Purification in Drosophila Heads and Ovaries. Bio Protoc 2:
Beerman, R W; Jongens, T A (2011) A non-canonical start codon in the Drosophila fragile X gene yields two functional isoforms. Neuroscience 181:48-66
Choi, Catherine H; Schoenfeld, Brian P; Bell, Aaron J et al. (2011) Pharmacological reversal of synaptic plasticity deficits in the mouse model of fragile X syndrome by group II mGluR antagonist or lithium treatment. Brain Res 1380:106-19
Bhogal, Balpreet; Jepson, James E; Savva, Yiannis A et al. (2011) Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein. Nat Neurosci 14:1517-24

Showing the most recent 10 out of 11 publications