La dysfonction striatopallide sous-tend un comportement répétitif dans un modèle d'autisme de Shank3 défectueux

Aperçu: G.M.

La protéine SH3 d'échafaudage postsynaptique SH3 et les domaines multiples de répression ankyrine 3 (SHANK3) sont essentiels au développement et à la fonction des synapses glutamatériques. La perturbation du gène codant pour SHANK3 a été fortement impliquée comme une cause monogénique de l'autisme, et les souris mutantes Shank3 montrent des gestes répétitifs et des déficits d'interaction sociale.  

Les résultats de l'étude démontrent directement l'existence de changements distincts entre 2 voies striatales dans un modèle d'autisme de la souris et indiquent que la perturbation indirecte de la bande striatale pourrait jouer un rôle de causalité dans le comportement répétitif des souris Shank3B mutantes.

J Clin Invest. 2017 Apr 17. pii: 87997. doi: 10.1172/JCI87997.

Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism

Wang W, Li C, Chen Q, van der Goes MS, Hawrot J, Yao AY, Gao X, Lu C, Zang Y, Zhang Q, Lyman K, Wang D, Guo B, Wu S, Gerfen CR, Fu Z, Feng G.

Abstract

The postsynaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (SHANK3) is critical for the development and function of glutamatergic synapses. Disruption of the SHANK3-encoding gene has been strongly implicated as a monogenic cause of autism, and Shank3 mutant mice show repetitive grooming and social interaction deficits. Although basal ganglia dysfunction has been proposed to underlie repetitive behaviors, few studies have provided direct evidence to support this notion and the exact cellular mechanisms remain largely unknown. Here, we utilized the Shank3B mutant mouse model of autism to investigate how Shank3 mutation may differentially affect striatonigral (direct pathway) and striatopallidal (indirect pathway) medium spiny neurons (MSNs) and its relevance to repetitive grooming behavior in Shank3B mutant mice. We found that Shank3 deletion preferentially affects synapses onto striatopallidal MSNs. Striatopallidal MSNs showed profound defects, including alterations in synaptic transmission, synaptic plasticity, and spine density. Importantly, the repetitive grooming behavior was rescued by selectively enhancing the striatopallidal MSN activity via a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD). Our findings directly demonstrate the existence of distinct changes between 2 striatal pathways in a mouse model of autism and indicate that the indirect striatal pathway disruption might play a causative role in repetitive behavior of Shank3B mutant mice.

PMID: 28414301

DOI: 10.1172/JCI87997