- Awarded: 2016
- Award Type: Explorer
- Award #: 455025
The brain abnormalities that lead to autism spectrum disorder (ASD) remain poorly understood. Convergent data from clinical and basic science research studies suggest that abnormalities in brain interneurons may contribute to the condition. These interneurons are also implicated in tics and Tourette syndrome, which are frequently comorbid with ASD.
Christopher Pittenger and his colleagues used molecular techniques in mice to ablate specific populations of interneurons in the striatum, the input nucleus of the basal ganglia. They then examined the mechanistic and behavioral consequences. Targeted ablation of either of two populations of striatal fast-spiking interneurons1 or cholinergic interneurons2 produced repetitive behaviors (reminiscent of tics) after stress, though not at baseline. Unpublished data show that simultaneous ablation of both populations of interneurons produces behavioral effects not seen after ablation of either population alone, including spontaneous repetitive behaviors and social deficits. These phenotypes are similar to what has been observed in several genetic mouse models of ASD. Strikingly, these effects are seen only in male mice. This parallels the epidemiology of ASD and Tourette syndrome, both of which are seen more often in males than in females.
The Pittenger lab plans to replicate and extend these preliminary findings, and to characterize mechanistic correlates at the level of striatal neuronal activity and molecular signaling. This work will refocus attention on interneurons of the basal ganglia as a locus of pathology in ASD and has the potential to identify new pathophysiological contributors. In particular, the finding of sexual dimorphism in the effects of interneuronal ablation promises to shed new light on the robust but unexplained observation that ASD is four times more common in males than in females.