title: Reduced Lateral Inhibition Impairs Olfactory Computations and Behaviors in a Drosophila Model of Fragile X Syndrome.
abstract: 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.
authors.affiliation: Neuroelectronics Research Flanders (NERF), KU Leuven, Kapeldreef 75, 3001 Leuven, Belgium; VIB Center for the Biology of Disease, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Franco
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Okray
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Gerit A
authors.initials: GA
authors.lastname: Linneweber
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Institut du Cerveau et de la Moelle Epinière (ICM) - Hôpital Pitié-Salpêtrière, UPMC, Sorbonne Universités, Inserm, CNRS, 47 Boulevard Hôpital, 75013 Paris, France. Electronic address: bassem.hassan@icm-institute.org.
authors.forename: Bassem A
authors.initials: BA
authors.lastname: Hassan
authors.affiliation: Neuroelectronics Research Flanders (NERF), KU Leuven, Kapeldreef 75, 3001 Leuven, Belgium; Kavli Institute for Systems Neuroscience and Centre for Neural Computation, NTNU, Olav Kyrres gate 9, 7030 Trondheim, Norway. Electronic address: emre.yaksi@ntnu.no.
authors.forename: Emre
authors.initials: E
authors.lastname: Yaksi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000502:physiology; D001522:Behavior, Animal; D002454:Cell Differentiation; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster / Q000502:physiology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000502:physiology*; D005600:Fragile X Syndrome / Q000503:physiopathology* / Q000523:psychology; D009415:Nerve Net / Q000502:physiology; D018034:Olfactory Receptor Neurons / Q000166:cytology / Q000502:physiology*; D012903:Smell / Q000502:physiology*; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D005680:gamma-Aminobutyric Acid; C467328:FMR1 protein, Drosophila
keywords: Drosophila melanogaster; antennal lobe; autism; calcium imaging; fragile X syndrome; fruit fly; lateral inhibition; mental disabilities; neural circuits; olfaction