title: 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.
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.
authors.affiliation: Biomedical Sciences Research Centre Alexander Fleming, 16672 Vari, Greece.
authors.forename: Alexandros K
authors.initials: AK
authors.lastname: Kanellopoulos
authors.forename: Ourania
authors.initials: O
authors.lastname: Semelidou
authors.forename: Andriana G
authors.initials: AG
authors.lastname: Kotini
authors.forename: Maria
authors.initials: M
authors.lastname: Anezaki
authors.forename: Efthimios M C
authors.initials: EM
authors.lastname: Skoulakis
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal; D050882:CREB-Binding Protein / Q000378:metabolism; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D004330:Drosophila; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007859:Learning Disabilities / Q000188:drug therapy / Q000235:genetics*; D008569:Memory Disorders / Q000188:drug therapy / Q000235:genetics*; D024521:Mushroom Bodies / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D050765:Qa-SNARE Proteins / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D050882:CREB-Binding Protein; D000242:Cyclic AMP; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D058988:Phosphodiesterase 4 Inhibitors; D011725:Pyridines; D050765:Qa-SNARE Proteins; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D020889:Rolipram; C121465:6-methyl-2-(phenylethynyl)pyridine