ABSTRACT
The involvement of parvalbumin (PV) interneurons in autism spectrum disorders (ASD) pathophysiology has been widely described without clearly elucidating how their dysfunctions could lead to ASD symptoms. The Cntnap2-/- mice, an ASD mouse model deficient for a major ASD susceptibility gene, display core ASD symptoms including motor stereotypies, which are directly linked to striatal dysfunction. This study reveals that striatal PV interneurons display hyperexcitability and hyperactivity in Cntnap2-/- mice, along with a reduced response in medium spiny neurons. We also provide evidence for a crucial role of striatal PV interneurons in motor stereotypies by demonstrating that their selective inhibition rescued a wild type-like phenotype. Our study identifies how PV interneuron dysfunctions disrupt striatal circuitry and drive the motor stereotypies in ASD.
ABSTRACT
Autism spectrum disorders (ASDs) are defined as a set of neurodevelopmental disorders and a lifelong condition. In mice, most of the studies focused on the developmental aspects of these diseases. In this paper, we examined the evolution of motor stereotypies through adulthood in the Shank3ΔC/ΔC mouse model of ASD, and their underlying striatal alterations, at 10 weeks, 20 weeks, and 40 weeks. We highlighted that motor stereotypies worsened at 40 weeks possibly carried by earlier striatal medium spiny neurons (MSN) alterations in GABAergic transmission and morphology. Moreover, we report that 20 weeks could be a critical time-point in the striatal-related ASD physiopathology, and we suggest that MSN alterations may not be the direct consequence of developmental issues, but rather be a consequence of other impairments occurring earlier.
