Erickson, C. A. | Search bioRxiv

bioRxiv2025

A human electrophysiological biomarker of Fragile X Syndrome is shared in V1 of Fmr1 KO mice and caused by loss of FMRP in cortical excitatory neurons

Predicting clinical therapeutic outcomes from preclinical animal studies remains an obstacle to developing treatments for neuropsychiatric disorders. Electrophysiological biomarkers analyzed consistently across species could bridge this divide. In humans, alpha oscillations in the resting state electroencephalogram (rsEEG) are altered in many disorders, but these disruptions have not yet been characterized in animal models. Here, we employ a uniform analytical method to show in males with fragile X syndrome (FXS) that the slowed alpha oscillations observed in adults are also present in children and in visual cortex of adult and juvenile Fmr1-/y mice. We find that alpha-like oscillations in mice reflect the differential activity of two classes of inhibitory interneurons, but the phenotype is caused by deletion of Fmr1 specifically in cortical excitatory neurons. These results provide a framework for studying alpha oscillation disruptions across species, advance understanding of a critical rsEEG signature in the human brain and inform the cellular basis for a putative biomarker of FXS.

neuroscience↗

bioRxiv2017

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

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.

neuroscience↗