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

Anubhuti Goel; Daniel A Cantu; Janna Guilfoyle; Gunvant R Chaudhari; Aditi Newadkar; Barbara Todisco; Diego de Alba; Nazim Kourdougli; Lauren M Schmitt; Ernest Pedapati; Craig A Erickson; Carlos Portera-Cailliau

doi:10.1038/s41593-018-0231-0

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

Nat Neurosci. 2018 Oct;21(10):1404-1411. doi: 10.1038/s41593-018-0231-0. Epub 2018 Sep 24.

Authors

Affiliations

¹ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
² Department of Psychiatry, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
³ Department of Neurology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁴ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. cpcailliau@mednet.ucla.edu.
⁵ Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. cpcailliau@mednet.ucla.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Animals
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
Choice Behavior / physiology
Discrimination, Psychological / physiology
Disease Models, Animal
Female
Fragile X Mental Retardation Protein / genetics
Fragile X Mental Retardation Protein / metabolism
Fragile X Syndrome / complications*
Fragile X Syndrome / diagnostic imaging
Fragile X Syndrome / genetics
Fragile X Syndrome / pathology*
Humans
Inhibition, Psychological
Learning Disabilities / etiology*
Male
Mice
Mice, Transgenic
Neurons / metabolism
Neurons / pathology*
Neuropil / metabolism
Neuropil / pathology
Oxygen / blood
Parvalbumins / genetics
Parvalbumins / metabolism*
Perceptual Disorders / etiology*
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism
Visual Cortex / diagnostic imaging
Visual Cortex / pathology*
Young Adult

Substances

Fmr1 protein, mouse
Parvalbumins
Receptors, G-Protein-Coupled
Fragile X Mental Retardation Protein
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Oxygen

Abstract

Publication types

MeSH terms

Substances

Grants and funding