Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models

Antoine, Michelle W.; Langberg, Tomer; Schnepel, Philipp; Feldman, Daniel E.

doi:10.1016/j.neuron.2018.12.026

Cited by 336 publications

(345 citation statements)

References 63 publications

(94 reference statements)

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“…In part, these problems may arise because some of the observed changes are the result of compensatory neuronal plasticity rather than true FMRP‐dependent biological pathways, and may therefore, differ with age, sex, and genetic background. More systematic future studies of the role of FMRP at different developmental states in multiple auditory nuclei may, therefore, resolve some of these issues …”

Section: Discussionmentioning

confidence: 99%

“…More systematic future studies of the role of FMRP at different developmental states in multiple auditory nuclei may, therefore, resolve some of these issues. 167 Finally, it may be possible to "borrow" useful approaches in other fields for studying FMRP regulation of auditory processing. For example, hearing loss often results in auditory perceptual disruptions, including hyperacusis, where moderate-intensity "everyday" sounds are perceived as intolerably loud or aversive.…”

Section: Directionsmentioning

confidence: 99%

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Mechanisms underlying auditory processing deficits in Fragile X syndrome

et al. 2020

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Autism spectrum disorders (ASD) are strongly associated with auditory hypersensitivity or hyperacusis (difficulty tolerating sounds). Fragile X syndrome (FXS), the most common monogenetic cause of ASD, has emerged as a powerful gateway for exploring underlying mechanisms of hyperacusis and auditory dysfunction in ASD. This review discusses examples of disruption of the auditory pathways in FXS at molecular, synaptic, and circuit levels in animal models as well as in FXS individuals. These examples highlight the involvement of multiple mechanisms, from aberrant synaptic development and ion channel deregulation of auditory brainstem circuits, to impaired neuronal plasticity and network hyperexcitability in the auditory cortex. Though a relatively new area of research, recent discoveries have increased interest in auditory dysfunction and mechanisms underlying hyperacusis in this disorder. This rapidly growing body of data has yielded novel research directions addressing critical questions regarding the timing and possible outcomes of human therapies for auditory dysfunction in ASD.

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Section: Discussionmentioning

confidence: 99%

Section: Directionsmentioning

confidence: 99%

Mechanisms underlying auditory processing deficits in Fragile X syndrome

et al. 2020

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“…Lower excitatory firing was apparent even though mice detected low contrast, static stimuli that drove neural activity far less vigorously than drifting, highcontrast stimuli typical of many studies of mouse V1 (Durand et al, 2016;Michaiel, Parker, & Niell, 2019). This highlights the need to not only compare neural circuit deficits across multiple mouse models of ASD (Antoine et al, 2019), but to also compare across multiple brain states, stimulus sets, and behavioral outcomes. Although we found that differences in arousal could not explain perceptual impairments, neural activity deficits may be more pronounced with behaviorally relevant engagement of neuromodulatory systems, an important topic for future investigations.…”

Section: Discussionmentioning

confidence: 97%

“…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. A third study suggests that these and multiple other ASD models internally compensate for deficits of excitatory and inhibitory activity, resulting in overall preserved sensory responsiveness (Antoine, Langberg, Schnepel, & Feldman, 2019); crucially, this study also did not measure neural activity deficits during sensory perceptual impairments. It thus remains unresolved if excitatory or inhibitory neural activity deficits underlie simultaneous perceptual impairments in ASD mouse models.…”

Section: Introductionmentioning

confidence: 96%

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

Rosario

Speed

Arrowood

et al. 2019

Preprint

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Sensory impairments are a core feature of autism spectrum disorder (ASD). These impairments affect visual perception, and have been hypothesized to arise from imbalances in excitatory and inhibitory activity in cortical circuits; however, there is little direct evidence testing this hypothesis with direct recordings of excitatory and inhibitory neural activity during relevant impairments of sensory perception. Here, we utilized a genetically relevant mouse model of ASD (CNTNAP2 -/knockout, KO) and recorded putative excitatory and inhibitory population spiking in primary visual cortex (V1) while measuring visual perceptual behavior. We found that KO mice showed quantitative impairments in both the speed and accuracy of visual perception. These impairments were simultaneously associated with diminished excitatory neuron activity and elevated low frequency network oscillations in superficial cortical layers 2/3 (L2/3). These results establish that perceptual deficits associated with ASD can arise from reduced sensory firing of excitatory rather than inhibitory neurons in cortical circuits.

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“…However, evidence for a widespread reduction in inhibition is either indirect or inconclusive. For example, there is evidence for decreased inhibition from genetic models of ASD in mice 7,[9][10][11] , but results in humans remain equivocal 8,[12][13][14][15][16][17] . An alternative is that modulatory processes that suppress neural responses, but do not rely directly on neural inhibition, are either disrupted or differentially engaged in ASD.…”

Section: Introductionmentioning

confidence: 99%

Weaker neural suppression in autism

Schallmo

Kolodny

Kale

et al. 2019

Preprint

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Increased neural excitation resulting from weakened inhibition is a leading hypothesis for the pathophysiology of autism. However, experimental support in humans remains equivocal. Alternatively, modulatory processes that suppress neural responses but do not specifically rely on inhibition may be impacted in ASD. Leveraging well-characterized suppressive neural circuits in the visual system, we used behavioral and fMRI tasks to demonstrate a significant reduction in neural suppression in young adults with ASD compared to neurotypical controls. We further tested the mechanism of this suppression by measuring levels of the inhibitory neurotransmitter GABA, and found no differences in GABA between groups. We show how a computational model that incorporates divisive normalization, as well as narrower top-down gain (that could result, for example, from a narrower window of attention), can explain our observations and divergent previous findings. Thus, weaker neural suppression in ASD may be attributable to differences in top-down processing, but not to differences in GABA levels.

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Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models

Cited by 336 publications

References 63 publications

Mechanisms underlying auditory processing deficits in Fragile X syndrome

Mechanisms underlying auditory processing deficits in Fragile X syndrome

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

Weaker neural suppression in autism

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