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

• Published in: Nature neuroscience Vol. 21; no. 10; pp. 1404 - 1411
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2018; Nature Publishing Group
• Subjects: 14/35; 14/69; 631/378; 631/378/1689; 631/378/1689/1373; 64/60; Activities of daily living; Adolescent; Adult; Analysis; Animal Genetics and Genomics; Animals; Autism; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Calcium; Calcium imaging; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Choice Behavior - physiology; Circuits; Discrimination, Psychological - physiology; Disease Models, Animal; Female; FMR1 protein; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X syndrome; Fragile X Syndrome - complications; Fragile X Syndrome - diagnostic imaging; Fragile X Syndrome - genetics; Fragile X Syndrome - pathology; Go/no-go discrimination learning; Human behavior; Human performance; Humans; Information processing; Inhibition, Psychological; Intellectual disabilities; Interneurons; Learning Disabilities - etiology; Male; Mice; Mice, Transgenic; Neurobiology; Neuroimaging; Neurons; Neurons - metabolism; Neurons - pathology; Neurophysiology; Neuropil - metabolism; Neuropil - pathology; Neurosciences; Orientation behavior; Oxygen - blood; Parvalbumin; Parvalbumins - genetics; Parvalbumins - metabolism; Perceptual Disorders - etiology; Perceptual learning; Photovoltaic cells; Receptors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Sensory integration; Sensory perception; Somatosensory cortex; Visual cortex; Visual Cortex - diagnostic imaging; Visual Cortex - pathology; Visual discrimination; Visual perception; Young Adult
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-018-0231-0

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. Goel et al found similar deficits in visual discrimination in humans and in a mouse model of FXS. In mice, a robust decrease in PV cell activity mediated this impairment, suggesting that manipulating inhibition may improve sensory processing in FXS.