Retinal alterations in a pre-clinical model of an autism spectrum disorder

Abstract

Background: Autism spectrum disorders (ASD) affect around 1.5% of people worldwide. Symptoms start around age 2, when children fail to maintain eye contact and to develop speech and other forms of communication. Disturbances in glutamatergic and GABAergic signaling that lead to synaptic changes and alter the balance between excitation and inhibition in the developing brain are consistently found in ASD. One of the hallmarks of these disorders is hypersensitivity to sensory stimuli; however, little is known about its underlying causes. Since the retina is the part of the CNS that converts light into a neuronal signal, we set out to study how it is affected in adolescent mice prenatally exposed to valproic acid (VPA), a useful tool to study ASD endophenotypes. Methods: Pregnant female mice received VPA (600 mg/kg, ip) or saline at gestational day 11. Their male adolescent pups (P29-35) were behaviorally tested for anxiety and social interaction. Proteins known to be related with ASD were quantified and visualized in their retinas by immunoassays, and retinal function was assessed by full-field scotopic electroretinograms (ERGs). Results: Early adolescent mice prenatally exposed to VPA displayed impaired social interest and increased anxiety-like behaviors consistent with an ASD phenotype. The expression of GABA, GAD, synapsin-1, and FMRP proteins were reduced in their retinas, while mGluR5 was increased. The a-wave amplitudes of VPA-exposed were smaller than those of CTR animals, whereas the b-wave and oscillatory potentials were normal. Conclusions: This study establishes that adolescent male mice of the VPA-induced ASD model have alterations in retinal function and protein expression compatible with those found in several brain areas of other autism models. These results support the view that synaptic disturbances with excitatory/inhibitory imbalance early in life are associated with ASD and point to the retina as a window to understand their subjacent mechanisms.

Atypical visual processing in a mouse model of autism

“…In another study of Fmr1 knockout mice, both a-wave and b-wave amplitudes in scotopic ERG were decreased 18 . Interestingly, a recent article reported that in the valproic acid induced mouse model of ASD, a-wave amplitudes were smaller yet b-wave amplitudes were normal in scotopic ERG 20 , similar to what we observed here. Thus, it appears that a decrease in a-wave amplitude is shared by idiopathic and syndromic mouse models of ASD.…”

“…Similar cortical recordings and behavioral tests could be applied to the BTBR mice as well, to further our understanding of the visual phenotype reported here. In addition, the anatomical and biochemical characterization of the retina and visual cortex, used in previous studies, provides a useful guide [15][16][17][18][19][20] , which could be followed in subsequent studies to investigate possible structural or biochemical rearrangements underlying the altered visual function in BTBR mice.…”

“…Establishing a reliable animal model for studying ASD-related alterations in visual processing might reveal the nature and underlying mechanisms of altered visual function observed in these patients. However, such studies in animal models of ASD have been limited 15 – 20 .…”

Light-Adapted Electroretinogram Differences in Autism Spectrum Disorder

“…Whilst abnormalities in glutamate receptor expression may explain the findings in ASD, there are possibilities that glutamate transporters and regulators of neuronal development, such as fragile-X mental retardation protein (FMRP) or mGLUR5, which regulates FMRP expression, may also be involved. Recent studies in a rodent model of ASD (Guimaraes-Souza et al 2019) found approximately 1.5 x more expression of FMRP and mGLUR5 proteins in the outer and inner plexiform layers which may contribute to an altered signaling between neurons in the outer and inner retina.…”

“…In addition, Constable et al (2016) examined the LA-ERG bwave amplitude and found it was smaller at certain flash strengths. The novel LA-ERG observations of Constable et al (2016) are supported by evidence of altered ERGs from rodent models of neurodevelopmental disorders in ASD (Zhang et al 2019;Guimaraes-Souza et al 2019), Fragile X syndrome (Rossignol et al 2014) and ADHD (Dai et al 2017). Additional benefits of studying the LA-ERG are that the greater complexity of the cone pathways makes the LA-ERG an excellent tool for probing the detail of a retina's response to light McCulloch et al 2019), and, because it does not require 20 minutes adapting to darkness, the LA-ERG is a quicker and more acceptable assay than the DA-ERG.…”