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

Abstract

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.

Interneuron-targeted disruption of SYNGAP1 alters sensory representations in neocortex and impairs sensory learning

“…Experiments in head-fixed mice performing whisker-guided sensory detection tasks are widely used for probing circuit dysfunction in autism models including pan-neuronal SYNGAP1 and interneuron-specific SHANK3 knock-out mice (Chen et al, 2020; Michaelson et al, 2018). Head-fixed preparations were also adopted in studies examining visual processing in autism models (Batista-Brito et al, 2017; Del Rosario et al, 2021; Goel et al, 2018). In most previous studies, however, neural activity and task performance were not measured simultaneously (except see (Del Rosario et al, 2021)).…”

“…Head-fixed preparations were also adopted in studies examining visual processing in autism models (Batista-Brito et al, 2017; Del Rosario et al, 2021; Goel et al, 2018). In most previous studies, however, neural activity and task performance were not measured simultaneously (except see (Del Rosario et al, 2021)). By combining two-photon calcium imaging and quantitative behavioral tasks in the same animal, we directly tested the relationships between neural activity and behavior in GABAergic SYNGAP1 haploinsufficiency.…”

Odor identification in novel olfactory environments is selectively impaired in a mouse model of autism

“…We chose a relatively complex training set (eight go mixtures and eight no-go mixtures) to promote generalization. We chose a go/no-go licking task because it is easy for WT mice to learn (Komiyama et al 2010) and it can also be learned by the Cntnap2 −/− mouse model of autism (Rosario et al 2020).…”

Cell-type specific transcriptomic signatures of neocortical circuit organization and their relevance to autism

“…For example, autism spectrum disorder (ASD) is hypothesized to result from an imbalance in the ratio of excitation to inhibition (E/I) within cortical circuits (Sohal and Rubenstein, 2019). Importantly, impairments that characterize ASD range from aberrant social behavior (entailing prefrontal circuits) (Yizhar et al, 2011) to sensory processing deficits (entailing visual cortical circuits) (Del Rosario et al, 2021). Thus, a tantalizing hypothesis is that in some instances ASD results from disruption of a canonical circuit motif that is repeated across functionally distinct regions.…”