Abstract
Autism spectrum disorders (ASD) are characterized by two seemingly unrelated symptom domains—deficits in social interactions and restrictive, repetitive patterns of behavioral output. Whether the diverse nature of ASD symptomatology represents distributed dysfunction of brain networks or abnormalities within specific neural circuits is unclear. Striatal dysfunction is postulated to underlie the repetitive motor behaviors seen in ASD, and neurological and brain-imaging studies have supported this assumption. However, as our appreciation of striatal function expands to include regulation of behavioral flexibility, motivational state, goal-directed learning, and attention, we consider whether alterations in striatal physiology are a central node mediating a range of autism-associated behaviors, including social and cognitive deficits that are hallmarks of the disease. This review investigates multiple genetic mouse models of ASD to explore whether abnormalities in striatal circuits constitute a common pathophysiological mechanism in the development of autism-related behaviors. Despite the heterogeneity of genetic insult investigated, numerous genetic ASD models display alterations in the structure and function of striatal circuits, as well as abnormal behaviors including repetitive grooming, stereotypic motor routines, deficits in social interaction and decision-making. Comparative analysis in rodents provides a unique opportunity to leverage growing genetic association data to reveal canonical neural circuits whose dysfunction directly contributes to discrete aspects of ASD symptomatology. The description of such circuits could provide both organizing principles for understanding the complex genetic etiology of ASD as well as novel treatment routes. Furthermore, this focus on striatal mechanisms of behavioral regulation may also prove useful for exploring the pathogenesis of other neuropsychiatric diseases, which display overlapping behavioral deficits with ASD.
Highlights
Reviewed by: Nicole Calakos, Duke University Medical Center, USA Lenora J
This review investigates multiple genetic mouse models of Autism spectrum disorders (ASD) to explore whether abnormalities in striatal circuits constitute a common pathophysiological mechanism in the development of autism-related behaviors
Comparative analysis in rodents provides a unique opportunity to leverage growing genetic association data to reveal canonical neural circuits whose dysfunction directly contributes to discrete aspects of ASD symptomatology
Summary
Moving from a Clinical to Molecular Characterization of Autism Spectrum Disorders. The earliest clinical descriptions of autism highlighted two symptom domains, focusing on social behaviors and the regulation of motor output. The striatal systems mediating these functions are thought to be segregated, with the dorsal medial striatum (roughly analogous to the caudate in humans) supporting goal-directed behavioral responding, the dorsal lateral striatum (analogous to the putamen) supporting automated behaviors and the nucleus accumbens mediating motivational states and reward processing (Yin and Knowlton, 2006; Balleine and O’Doherty, 2010; Floresco, 2015) Both the dorsal medial striatum and nucleus accumbens are key neural circuits for maintaining flexible behavioral responding under changing reward contingencies (Kehagia et al, 2010). Song directed at potential female mates is precise—a byproduct of a more stereotyped basal ganglia firing pattern, which may result from cue-dependent increased dopamine release within striatum (Gale and Perkel, 2005; Leblois et al, 2010) While it is currently unclear if the mammalian striatum is involved in the regulation of behavioral variability, it is easy to see how deficits in this function could contribute to the restricted behavioral output observed in ASD. Our understanding of pathophysiological mechanisms relies on the ability to manipulate
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