title: The fragile X mental retardation protein developmentally regulates the strength and fidelity of calcium signaling in Drosophila mushroom body neurons.
abstract: Fragile X syndrome (FXS) is a broad-spectrum neurological disorder characterized by hypersensitivity to sensory stimuli, hyperactivity and severe cognitive impairment. FXS is caused by loss of the fragile X mental retardation 1 (FMR1) gene, whose FMRP product regulates mRNA translation downstream of synaptic activity to modulate changes in synaptic architecture, function and plasticity. Null Drosophila FMR1 (dfmr1) mutants exhibit reduced learning and loss of protein synthesis-dependent memory consolidation, which is dependent on the brain mushroom body (MB) learning and memory center. We targeted a transgenic GFP-based calcium reporter to the MB in order to analyze calcium dynamics downstream of neuronal activation. In the dfmr1 null MB, there was significant augmentation of the calcium transients induced by membrane depolarization, as well as elevated release of calcium from intracellular organelle stores. The severity of these calcium signaling defects increased with developmental age, although early stages were characterized by highly variable, low fidelity calcium regulation. At the single neuron level, both calcium transient and calcium store release defects were exhibited by dfmr1 null MB neurons in primary culture. Null dfmr1 mutants exhibit reduced brain mRNA expression of calcium-binding proteins, including calcium buffers calmodulin and calbindin, predicting that the inability to appropriately sequester cytosolic calcium may be the common mechanistic defect causing calcium accumulation following both influx and store release. Changes in the magnitude and fidelity of calcium signals in the absence of dFMRP likely contribute to defects in neuronal structure/function, leading to the hallmark learning and memory dysfunction of FXS.
authors.affiliation: Department of Biological Sciences, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Tessier
authors.forename: Kendal
authors.initials: K
authors.lastname: Broadie
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics*; D004331:Drosophila melanogaster; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D008564:Membrane Potentials / Q000235:genetics; D024521:Mushroom Bodies / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; C467328:FMR1 protein, Drosophila