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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.

Original publication




Journal article


Curr Biol

Publication Date





1111 - 1123


Drosophila melanogaster, antennal lobe, autism, calcium imaging, fragile X syndrome, fruit fly, lateral inhibition, mental disabilities, neural circuits, olfaction, Animals, Animals, Genetically Modified, Behavior, Animal, Cell Differentiation, Disease Models, Animal, Drosophila Proteins, Drosophila melanogaster, Fragile X Mental Retardation Protein, Fragile X Syndrome, Nerve Net, Olfactory Receptor Neurons, Smell, Synaptic Transmission, gamma-Aminobutyric Acid