Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome

Abstract

Many people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABAA receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.

Atypical retinal function in a mouse model of Fragile X syndrome

“…For example, in Fragile X syndrome, a disorder strongly linked to ASD, symptoms include reduced temporal resolution of vision in infants (Farzin, Rivera, and Whitney 2011), lower contrast sensitivity (Kogan et al 2004), visual hypersensitivity (Raspa et al 2018), and sleep disturbances such as night waking (Hagerman et al 2017). Some of these symptoms are homologous in the mouse model of Fragile X syndrome, which supports the idea that “low level” retinal processing may shape symptoms (Saré et al 2017; Goel et al 2018; Perche et al 2021; Felgerolle et al 2019; Yang et al 2022).…”

Topography and Ensemble Activity in the Auditory Cortex of a Mouse Model of Fragile X Syndrome

“…Furthermore, interneurons and pyramidal neurons as well as pyramidal neurons themselves are desynchronized ( Paluszkiewicz et al, 2011 ; Kourdougli et al, 2023 ), and sensory encoding precision is reduced ( Domanski et al, 2019 ). In the visual cortex, hyperconnectivity and increased dendritic complexity ( Haberl et al, 2015 ; C. Yang et al, 2022 ) as well as increased spine turnover ( Ishii et al, 2018 ) were reported. Similar alterations have been observed in AC circuits as well, including an increase in spine density, with immature spine morphology ( Lee et al, 2019 ), altered GABAergic signaling ( Song et al, 2022 ), abnormal perineuronal net development around PV interneurons ( Lovelace et al, 2016 ; Wen et al, 2018 ), and local hyperconnectivity, but long-range hypoconnectivity ( Haberl et al, 2015 ).…”

Gene therapy using human FMRP isoforms driven by the human FMR1 promoter rescues fragile X syndrome mouse deficits

“…found that injecting serotype 9 AAVs into P0 and P35 mice to re-express murine FMRP isoform 1 (driven by the CMV promoter) ameliorated visual hypersensitivity in Fmr1 KO mice. 15 …”

“…Overall, these studies demonstrate that restoration of FMRP at least partially reversed altered biochemical and physiological features and attenuated behavioral deficits in rodent FXS models. 2 , 12 , 13 , 14 , 15 However, all these studies used rodent FMRP and the expression was driven by promoters other than the human FMR1 promoter. To apply AAV gene therapy for FXS clinical tests in the future, the therapeutic efficacy of human FMRP expression in appropriate cells and at physiological levels, preferably driven by the human FMR1 gene promoter should be determined.…”