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Kanellopoulos, A.K., Semelidou, O., Kotini, A.G., Anezaki, M., Skoulakis, E.M. (2012). Learning and memory deficits consequent to reduction of the fragile x mental retardation protein result from metabotropic glutamate receptor-mediated inhibition of cAMP signaling in Drosophila.  J. Neurosci. 32(38): 13111--13124.
FlyBase ID
FBrf0219485
Publication Type
Research paper
Abstract

Loss of the RNA-binding fragile X protein [fragile X mental retardation protein (FMRP)] results in a spectrum of cognitive deficits, the fragile X syndrome (FXS), while aging individuals with decreased protein levels present with a subset of these symptoms and tremor. The broad range of behavioral deficits likely reflects the ubiquitous distribution and multiple functions of the protein. FMRP loss is expected to affect multiple neuronal proteins and intracellular signaling pathways, whose identity and interactions are essential in understanding and ameliorating FXS symptoms. We used heterozygous mutants and targeted RNA interference-mediated abrogation in Drosophila to uncover molecular pathways affected by FMRP reduction. We present evidence that FMRP loss results in excess metabotropic glutamate receptor (mGluR) activity, attributable at least in part to elevation of the protein in affected neurons. Using high-resolution behavioral, genetic, and biochemical analyses, we present evidence that excess mGluR upon FMRP attenuation is linked to the cAMP decrement reported in patients and models, and underlies olfactory associative learning and memory deficits. Furthermore, our data indicate positive transcriptional regulation of the fly fmr1 gene by cAMP, via protein kinase A, likely through the transcription factor CREB. Because the human Fmr1 gene also contains CREB binding sites, the interaction of mGluR excess and cAMP signaling defects we present suggests novel combinatorial pharmaceutical approaches to symptom amelioration upon FMRP attenuation.

PubMed ID
PubMed Central ID
PMC6621471 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    J. Neurosci.
    Title
    Journal of Neuroscience
    Publication Year
    1981-
    ISBN/ISSN
    0270-6474 1529-2401
    Data From Reference
    Aberrations (2)
    Alleles (14)
    Balancers (2)
    Genes (5)
    Human Disease Models (2)
    Insertions (3)
    Transgenic Constructs (7)