Modeling autism-relevant behavioral phenotypes in rats and mice

Abstract

Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets.

Sex‐specific autistic endophenotypes induced by prenatal exposure to valproic acid involve anandamide signalling

“…Consistent with this possibility, at infancy, male but not female pups prenatally exposed to VPA showed communicative deficits, since they emitted less USVs than control pups when isolated from the dam and siblings. In rodents, these USVs play a fundamental role in mother–offspring interactions, as they induce maternal retrieval and elicit care‐giving behaviours in the dam (Servadio et al ., ).…”

“…Based on thsee clinical observations, prenatal VPA exposure in rodents is a widely used environmental preclinical model of ASD with face and construct validity (Williams et al ., ; Schneider and Przewlocki, ; Wagner et al ., ; Roullet et al ., ; Sabers et al ., ; Servadio et al ., , ). This model, however, has been mainly validated and used in male rodents.…”

Altered Auditory Processing, Filtering, and Reactivity in theCntnap2Knock-Out Rat Model for Neurodevelopmental Disorders

“…Our results also differ from studies on Fmr1 knock-out mice and rats, a model for fragile X syndrome. With respect to the ABR, fragile X mice show smaller wave I and III peak amplitudes and no latency differences (Rotschafer et al, 2015). Behaviorally, Fmr1 knock-out rats show typical startle responses and no significant PPI differences.…”

“…prepulse stimulus (10 ms white noise at either 75 dB SPL or 85 dB SPL; 5 ms rise/fall time). During a continuous background noise (60 dB SPL white noise), prepulses were presented 30 or 100 ms (i.e., the interstimulus interval, ISI) before the startle stimulus for maximum PPI (Ison et al, 1973;Graham, 1975;Graham and Murray, 1977;Hoffman and Ison, 1980;Valsamis and Schmid, 2011;Typlt et al, 2013;Pinnock et al, 2015;Zaman et al, 2017). In total, the animals were randomly presented 10 trials of each stimulus type (startle alone; 75 dB at 30 ms ISI; 75 dB at 100 ms ISI, 85 dB at 30 ms ISI, and 85 dB at 100 ms ISI), with the trials separated by a randomly varying ITIs (12, 15 or 18 s; see Fig.…”

Risk factors in autism: Thinking outside the brain

“…Animal models are increasingly utilized to investigate the intricate processes and mechanisms underlying ASD behaviors and phenotypes, and they are necessary for any kind of drug or therapeutic testing [71]. Both rodent and non-human primate models of maternal immune activation (MIA) have shown that even in the absence of overt infection, activation of the maternal immune system using viral and bacterial mimics as well as the cytokine IL-6 can result in behavioral changes in the offspring [72–74].…”