Interneuron dysfunction in the fragile X mouse model of autism

Speaker: Carlos Portera-Cailliau, M.D., Ph.D.
Professor of Neurology & Neurobiology, David Geffen School of Medicine, University of California, Los Angeles
Host: Dr. Elly Nedivi
Date: September 16, 2020

Talk title: Interneuron dysfunction in the fragile X mouse model of autism

Abstract: To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we have adopted a symptom-to-circuit approach in theFmr1-/-mouse model of Fragile X syndrome (FXS).  Using a ‘go/no-go’ visual discrimination task and in vivo 2-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons in primary visual cortex, and a decrease in the activity of parvalbumin (PV) interneurons.  Restoring visually evoked activity in PV cells in Fmr1-/-micewith a chemogenetic (DREADD) strategy was sufficient to rescue their behavioral performance.  Strikingly, human subjects with FXS exhibit similar impairments in visual discrimination as Fmr1-/- mice.  These results suggest that manipulating inhibition may help sensory processing in FXS. More recently, we find that task performance of Fmr1-/- mice is impaired in the presence of visual or auditory distractors, suggesting that sensory hyperarousal may affect perceptual learning in autism, a problem we link to dysfunction of VIP interneurons.