Disruption of visual circuit formation and refinement in a mouse model of autism

Abstract

Aberrant connectivity is believed to contribute to the pathophysiology of autism spectrum disorder (ASD). Recent neuroimaging studies have increasingly identified such impairments in patients with ASD, including alterations in sensory systems. However, the cellular substrates and molecular underpinnings of disrupted connectivity remain poorly understood. Utilizing eye‐specific segregation in the dorsal lateral geniculate nucleus (dLGN) as a model system, we investigated the formation and refinement of precise patterning of synaptic connections in the BTBR T + tf/J (BTBR) mouse model of ASD. We found that at the neonatal stage, the shape of the dLGN occupied by retinal afferents was altered in the BTBR group compared to C57BL/6J (B6) animals. Notably, the degree of overlap between the ipsi‐ and contralateral afferents was significantly greater in the BTBR mice. Moreover, these abnormalities continued into mature stage in the BTBR animals, suggesting persistent deficits rather than delayed maturation of axonal refinement. Together, these results indicate disrupted connectivity at the synaptic patterning level in the BTBR mice, suggesting that in general, altered neural circuitry may contribute to autistic behaviours seen in this animal model. In addition, these data are consistent with the notion that lower‐level, primary processing mechanisms contribute to altered visual perception in ASD. Autism Res 2017, 10: 212–223. © 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.

The BTBR mouse model of idiopathic autism – Current view on mechanisms

“…Inter-hemispheric connectivity was found to be present (synchronous rsfMRI signal) in the area of the visual cortex, but detailed analysis employing recombinant rabies virus tracing found no evidence for monosynaptic connections between the two hemispheres in this region. A recent work by Cheng and collaborators (2016) showed, however, that the patterning of retinal fibers within the dorsal lateral geniculate nucleus of both neonatal and adult BTBR mice was disrupted, with a much higher degree of overlap of ipsi- and contralateral fibers, than in B6 mice. Generally, however, aberrations in ipsilateral connections were found in the fronto-cortical regions, but not in the posterior parts of the cortex, and for subcortical fronto-thalamic and striatal fibers.…”

Metabolic Dysfunction Underlying Autism Spectrum Disorder and Potential Treatment Approaches

“…BTBR mice display deficits in social interaction and communication assays and exhibit repetitive and stereotyped behaviors. During the relatively short time since its discovery as an ASD model, the BTBR strain has been increasingly used to study the etiology and to uncover potential interventions for ASD (Moy et al, 2007 ; McFarlane et al, 2008 ; Llaneza et al, 2010 ; Ruskin et al, 2013 ; Cheng et al, 2016 ; Mychasiuk and Rho, 2016 ; Newell et al, 2016 ). Ruskin and colleagues reported that the BTBR mice showed decreased sociability in the three-chamber test, decreased self-directed repetitive behavior, and improved social communication in a food preference assay after being fed a KD (Ruskin et al, 2013 ).…”

Intranasal oxytocin administration rescues neonatal thermo-sensory deficit in mouse model of Autism

“…However, atypical sensory reactivity represents early markers of autism and are predictive of social-communication deficits and repetitive behaviors in childhood. Although recent findings performed in mouse ASD genetic models report sensory deficits(Chelini et al, 2019; Cheng et al, 2017; Drapeau et al, 2018; Huang et al, 2019; Orefice et al, 2016; Siemann et al, 2017), they were explored during juvenile or adult period. Whether sensory dysfunctions might be present at the early life stage is something unknown.…”

“…Much of research in animal models of syndromic and non-syndromic forms of ASDs has focused on the social and cognitive difficulties and their underlying mechanisms (Robertson and Baron-Cohen, 2017). Recent increasing evidences suggest that sensory traits such as tactile, visual, auditory, olfactory, gustatory and heat abnormalities (Chelini et al, 2019; Cheng et al, 2017; Drapeau et al, 2018; Huang et al, 2019; Orefice et al, 2016; Siemann et al, 2017) are present in ASD models, yet the existence of sensory dysfunctions during early life period have been unexplored.…”