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Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible.

  • Author(s): Goel, Anubhuti;
  • Cantu, Daniel A;
  • Guilfoyle, Janna;
  • Chaudhari, Gunvant R;
  • Newadkar, Aditi;
  • Todisco, Barbara;
  • de Alba, Diego;
  • Kourdougli, Nazim;
  • Schmitt, Lauren M;
  • Pedapati, Ernest;
  • Erickson, Craig A;
  • Portera-Cailliau, Carlos
  • et al.
Abstract

To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we adopted a symptom-to-circuit approach in the Fmr1-knockout (Fmr1-/-) mouse model of Fragile X syndrome. Using a go/no-go task and in vivo two-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons and with a decrease in the activity of parvalbumin interneurons in primary visual cortex. Restoring visually evoked activity in parvalbumin cells in Fmr1-/- mice with a chemogenetic strategy using designer receptors exclusively activated by designer drugs was sufficient to rescue their behavioral performance. Strikingly, human subjects with Fragile X syndrome exhibit impairments in visual discrimination similar to those in Fmr1-/- mice. These results suggest that manipulating inhibition may help sensory processing in Fragile X syndrome.

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