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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086902-07
Application #
8225215
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Krasnewich, Donna M
Project Start
2004-09-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
7
Fiscal Year
2012
Total Cost
$341,546
Indirect Cost
$118,796
Name
University of Pennsylvania
Department
Genetics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Monyak, R E; Emerson, D; Schoenfeld, B P et al. (2016) Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model. Mol Psychiatry :
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
Pepper, Anita; Bhogal, Balpreet; Jongens, Thomas (2012) Tandem Affinity Purification in Drosophila Heads and Ovaries. Bio Protoc 2:
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
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
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

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