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.
Highlights
Sensory processing abnormalities in fragile X syndrome (FXS) and other autism-related disorders seriously affect people’s lives in the form of hyperactivity, anxiety, and communication and cognitive difficulties
To study whether enhanced local connectivity was accompanied by a change in structure, we examined the morphological complexity of Fmr1KO primary visual cortex (V1) neurons using micro-optical sectioning tomography (MOST) (Li, et al, 2010)
The activation of γ-aminobutyric acid (GABA) receptors in V1 can reverse visual hypersensitivity in Fmr1KO mice. These results demonstrate that the inactivation of fragile-X mental retardation 1 (Fmr1) expression in V1 neurons was sufficient to induce enhanced responsiveness to low-intensity stimuli, which was accompanied by enhanced local functional connectivity independent of sensory inputs and lateral/upper modulations originating from the upstream brain regions
Summary
Sensory processing abnormalities in fragile X syndrome (FXS) and other autism-related disorders seriously affect people’s lives in the form of hyperactivity, anxiety, and communication and cognitive difficulties. Hypersensitivity to sensory stimuli is a prominent feature of both FXS and autism spectrum disorder (ASD) (Sinclair et al, 2017) and has been seen in many different brain areas, such as the auditory cortex, somatosensory cortex, and visual cortex (Molen et al, 2012a; Molen et al, 2012b; Rais et al, 2018). In FXS and ASD patients, abnormalities in low-level visual perception and processing have been linked to impaired recognition of facial expression and social interaction (Dakin and Frith 2005). FXS patients exhibit abnormal responses, including both hypoand hyper-sensitivity, to external stimuli such as sound, touch, or visual avoidance (Molen et al, 2012a; Molen et al, 2012b; Rais et al, 2018). The neurological mechanisms of sensory abnormalities in FXS and ASD, especially visual impairment, remain unclear
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