A human electrophysiological signature of Fragile X pathophysiology is shared in V1 of Fmr1-/y mice
Predicting clinical therapeutic outcomes from animal studies using conserved electrophysiological phenotypes could facilitate developing treatments for neuropsychiatric disorders. Alpha oscillations in human resting-state electroencephalogram recordings are altered in many disorders, but whether these disruptions exist in mouse models is unknown. Here, we employed a uniform analytical method to show in males with fragile X syndrome (FXS) that alpha oscillations in humans and alpha-like oscillations in the visual cortex of Fmr1<sup>-/y</sup> mice are slowed, with a stronger phenotype in adults than juveniles and a juvenile-specific power phenotype in both species. We find that alpha-like oscillations are disrupted by deletion of Fmr1 in cortical excitatory neurons and glia, reflect differential activity of two classes of GABAergic interneurons, and are more sensitive to activation of GABA<sub>B</sub> receptors by Arbaclofen in wild-type than Fmr1<sup>-/y</sup> mice. Our framework reveals evolutionary conservation of alpha oscillation disruptions, enables a deeper understanding of FXS pathophysiology, and narrows the gap between treatment promise and practice.
Authors
- Francesca A. Chaloner (ORCID: https://orcid.org/0000-0003-2707-4539)
- Mark F. Bear (ORCID: https://orcid.org/0000-0002-9903-2541)
- Jordan E. Norris (ORCID: https://orcid.org/0000-0002-4438-3416)
- Çiğdem Gelegen
- Lauren E. Ethridge (ORCID: https://orcid.org/0000-0003-0601-6911)
- Maia Lee (ORCID: https://orcid.org/0000-0002-5992-9477)
- Carol L. Wilkinson (ORCID: https://orcid.org/0000-0002-4694-8564)
- Maxwell J. Heinrich (ORCID: https://orcid.org/0009-0004-2368-3470)
- Sara S. Kornfeld-Sylla
- Michael Khela
- Lauren M. Schmitt
- Peter S. B. Finnie
- Craig A. Erickson
- Sam F. Cooke
Institutions
- Tufts University (US)
- Cincinnati Children's Hospital Medical Center (US)
- Rush University Medical Center (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- McGovern Institute for Brain Research (US)
- King's College London (GB)
- University of Toronto (CA)
- Phelan-McDermid Syndrome Foundation (US)
- Institute of Cognitive and Brain Sciences (US)
- Occupational Cancer Research Centre (CA)
- Rome Foundation (US)
- University of Oklahoma Health Sciences Center (US)
- Massachusetts Institute of Technology (US)
- University of Oklahoma (US)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-09
- DOI
- https://doi.org/10.1038/s41467-026-69243-0
- Citations
- 1
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 30.93