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

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.

Mechanisms underlying auditory processing deficits in Fragile X syndrome

“…Recent studies have provided evidence for perceptual learning or discrimination deficits in Fmr1 knockout mice in both the tactile and visual domains . Although fewer studies have examined auditory perceptual learning in FXS models, there is evidence for impaired auditory‐cued fear conditioning in Fmr1 knockout mice .…”

“…Recent studies have provided evidence for perceptual learning or discrimination deficits in Fmr1 knockout mice in both the tactile 161,162 and visual domains. 163 Although fewer studies have examined auditory perceptual learning in FXS models, there is evidence for impaired auditory-cued fear conditioning in Fmr1 knockout mice. 164,165 It is not clear, however, whether this impairment is more cognitive than perceptual in nature, because Fmr1 knockout mice exhibit impairment on a variety of associative learning paradigms that are not dependent on auditory cues.…”

Diminished cortical excitation and elevated inhibition during perceptual impairments in a mouse model of autism

“…However, little direct evidence for this hypothesis has been measured from identified excitatory and inhibitory neurons during quantifiable behavioral impairments. One recent study found that inhibitory neurons are more perturbed than excitatory neurons in superficial cortical layers 2/3 (L2/3) in a Fragile X syndrome mouse model of ASD (Goel et al, 2018). However, another study of ASD model mice observed reduced and poorly coordinated excitatory activity in frontal cortex of CNTNAP2 -/-KO mice (Lazaro et al, 2019), but these excitatory activity deficits were not measured during sensory impairments or behavior.…”

Differential processing and habituation in distinct spatial frequency channels in V1 of a mouse model of fragile X syndrome

“…Overall, our findings suggest that altered processing in distinct SF channels might contribute to altered visual perception and learning in FX and autism. that sensory alterations may be predictive of social communication deficits later in life in autism (Boyd et al, 2010;Turner-Brown et al, 2012).Both human and animal studies provide evidence that there is impaired information processing in early sensory areas in both autism and FX (Goel et al, 2018;Rais et al, 2018). Sensory hypersensitivity and reduced adaptation to sensory stimuli are some of the hallmark perceptual impairments in autism.…”

“…Both human and animal studies provide evidence that there is impaired information processing in early sensory areas in both autism and FX (Goel et al, 2018;Rais et al, 2018). Sensory hypersensitivity and reduced adaptation to sensory stimuli are some of the hallmark perceptual impairments in autism.…”