Impaired perceptual learning in Fragile X syndrome is mediated by parvalbumin neuron dysfunction in V1 and is reversible.

Goel, A.; Cantu, D.; Guilfoyle, J.; Chaudhari, G. R.; Newadkar, A.; Todisco, B.; Alba, D. d.; Kourdougli, N.; Schmitt, L. M.; Pedapati, E.; Erickson, C. A.; Portera-Cailliau, C.

doi:10.1101/217414

bioRxiv · 10.1101/217414

Impaired perceptual learning in Fragile X syndrome is mediated by parvalbumin neuron dysfunction in V1 and is reversible.

Goel, A.·Cantu, D.·Guilfoyle, J.·Chaudhari, G. R.·Newadkar, A.·Todisco, B.·Alba, D. d.·Kourdougli, N.·Schmitt, L. M.·Pedapati, E.·Erickson, C. A.·Portera-Cailliau, C.

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Abstract

Atypical sensory processing is a core characteristic in autism spectrum disorders1 that negatively impacts virtually all activities of daily living. Sensory symptoms are predictive of the subsequent appearance of impaired social behavior and other autistic traits2, 3. Thus, a better understanding of the changes in neural circuitry that disrupt perceptual learning in autism could shed light into the mechanistic basis and potential therapeutic avenues for a range of autistic symptoms2. Likewise, the lack of directly comparable behavioral paradigms in both humans and animal models currently limits the translational potential of discoveries in the latter. We adopted a symptom-to-circuit approach to uncover the circuit-level alterations in the Fmr1-/- mouse model of Fragile X syndrome (FXS) that underlie atypical visual discrimination in this disorder4, 5. Using a go/no-go task and in vivo 2-photon calcium imaging in primary visual cortex (V1), we find that impaired discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons, and a decrease in the activity of parvalbumin (PV) interneurons in V1. Restoring visually evoked activity in PV cells in Fmr1-/- mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioral performance. Finally, we found that human subjects with FXS exhibit strikingly similar impairments in visual discrimination as Fmr1-/- mice. We conclude that manipulating orientation tuning in autism could improve visually guided behaviors that are critical for playing sports, driving or judging emotions.

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Goel, A., Cantu, D., Guilfoyle, J., Chaudhari, G. R., Newadkar, A., Todisco, B., Alba, D. d., Kourdougli, N., Schmitt, L. M., Pedapati, E., Erickson, C. A., Portera-Cailliau, C.. 2017-11-13. Impaired perceptual learning in Fragile X syndrome is mediated by parvalbumin neuron dysfunction in V1 and is reversible.. https://doi.org/10.1101/217414

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