Targeted Interneuron Depletion in the Dorsal Striatum Produces Autism-like Behavioral Abnormalities in Male but Not Female Mice

Abstract

BackgroundInterneuronal pathology is implicated in many neuropsychiatric disorders, including autism spectrum disorder (ASD) and Tourette syndrome (TS). Interneurons of the striatum, including the parvalbumin-expressing fast-spiking interneurons (FSIs) and the large cholinergic interneurons (CINs), are affected in patients with TS and in preclinical models of both ASD and TS. MethodsTo test the causal importance of these neuronal abnormalities, we recapitulated them in vivo in developmentally normal mice using a combination transgenic–viral strategy for targeted toxin-mediated ablation. ResultsWe found that conjoint ~50% depletion of FSIs and CINs in the dorsal striatum of male mice produces spontaneous stereotypy and marked deficits in social interaction. Strikingly, these behavioral effects are not seen in female mice; because ASD and TS have a marked male predominance, this observation reinforces the potential relevance of the finding to human disease. Neither of these effects is seen when only one or the other interneuronal population is depleted; ablation of both is required. Depletion of FSIs, but not of CINs, also produces anxiety-like behavior, as has been described previously. Behavioral pathology in male mice after conjoint FSI and CIN depletion is accompanied by increases in activity-dependent signaling in the dorsal striatum; these alterations were not observed after disruption of only one interneuron type or in doubly depleted female mice. ConclusionsThese data indicate that disruption of CIN and FSI interneurons in the dorsal striatum is sufficient to produce network and behavioral changes of potential relevance to ASD, in a sexually dimorphic manner.