Reduced Lateral Inhibition Impairs Olfactory Computations and Behaviors in a Drosophila Model of Fragile X Syndrome

Curr Biol. 2017 Apr 24;27(8):1111-1123. doi: 10.1016/j.cub.2017.02.065. Epub 2017 Mar 30.


Fragile X syndrome (FXS) patients present neuronal alterations that lead to severe intellectual disability, but the underlying neuronal circuit mechanisms are poorly understood. An emerging hypothesis postulates that reduced GABAergic inhibition of excitatory neurons is a key component in the pathophysiology of FXS. Here, we directly test this idea in a FXS Drosophila model. We show that FXS flies exhibit strongly impaired olfactory behaviors. In line with this, olfactory representations are less odor specific due to broader response tuning of excitatory projection neurons. We find that impaired inhibitory interactions underlie reduced specificity in olfactory computations. Finally, we show that defective lateral inhibition across projection neurons is caused by weaker inhibition from GABAergic interneurons. We provide direct evidence that deficient inhibition impairs sensory computations and behavior in an in vivo model of FXS. Together with evidence of impaired inhibition in autism and Rett syndrome, these findings suggest a potentially general mechanism for intellectual disability.

Keywords: Drosophila melanogaster; antennal lobe; autism; calcium imaging; fragile X syndrome; fruit fly; lateral inhibition; mental disabilities; neural circuits; olfaction.

MeSH terms

  • Animals
  • Animals, Genetically Modified / physiology
  • Behavior, Animal*
  • Cell Differentiation
  • Disease Models, Animal*
  • Drosophila Proteins / physiology*
  • Drosophila melanogaster / physiology*
  • Fragile X Mental Retardation Protein / physiology*
  • Fragile X Syndrome / physiopathology*
  • Fragile X Syndrome / psychology
  • Nerve Net / physiology
  • Olfactory Receptor Neurons / cytology
  • Olfactory Receptor Neurons / physiology*
  • Smell / physiology*
  • Synaptic Transmission
  • gamma-Aminobutyric Acid / metabolism


  • Drosophila Proteins
  • FMR1 protein, Drosophila
  • Fragile X Mental Retardation Protein
  • gamma-Aminobutyric Acid