The fragile X mental retardation protein developmentally regulates the strength and fidelity of calcium signaling in Drosophila mushroom body neurons

Neurobiol Dis. 2011 Jan;41(1):147-59. doi: 10.1016/j.nbd.2010.09.002. Epub 2010 Sep 16.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / physiology
  • Calcium Signaling / genetics*
  • Calcium-Binding Proteins / genetics
  • Cells, Cultured
  • Drosophila Proteins / deficiency
  • Drosophila Proteins / genetics*
  • Drosophila melanogaster*
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism
  • Gene Expression Regulation, Developmental / physiology*
  • Membrane Potentials / genetics
  • Mushroom Bodies / cytology
  • Mushroom Bodies / growth & development
  • Mushroom Bodies / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*

Substances

  • Calcium-Binding Proteins
  • Drosophila Proteins
  • FMR1 protein, Drosophila
  • Fragile X Mental Retardation Protein
  • Calcium