Effects of Chemogenetic Inhibition of D1 or D2 Receptor-Containing Neurons of the Substantia Nigra and Striatum in Mice With Tourette Syndrome.

Lixue Lin,Lingling Yu,Shuang Wu,Hong Zhang,Yang Shu,Hongchun Xiang,Wen Su,He Zhu,Yuye Lan,Man Li,Yan Ma,Tengfei Hou,Wangyixuan Wan

doi:10.3389/fnmol.2021.779436

Abstract

As tourette syndrome (TS) is a common neurobehavioral disorder, the primary symptoms of which include behavioral stereotypies. Dysfunction of the substantia nigra–striatum network could be the main pathogenesis of TS, which is closely associated with dopamine (DA) and its receptors. TS is often resistant to conventional treatments. Therefore, it is necessary to investigate the neurobiological mechanisms underlying its pathogenesis. In this study, we investigated whether chemogenetic activation or inhibition of dopaminergic D1 receptor (D1R)- or D2 receptor (D2R)-containing neurons in the substantia nigra pars compacta (SNpc) or dorsal striatum (dSTR) affected the stereotyped behavior and motor functions of TS mice. Intraperitoneal injection of 3,3′-iminodipropionitrile (IDPN) was used to induce TS in mice. Stereotyped behavior test and open-field, rotarod, and grip strength tests were performed to evaluate stereotyped behavior and motor functions, respectively. Immunofluorescence labeling was used to detect the co-labeling of virus fluorescence and D1R or D2R. We found that chemogenetic inhibition of D1R- or D2R-containing neurons in the SNpc and dSTR alleviated behavioral stereotypies and motor functions in TS mice. Chemogenetic activation of D1R-containing neurons in the dSTR aggravated behavioral stereotypies and motor functions in vehicle-treated mice, but neither was aggravated in TS mice. In conclusion, chemogenetic inhibition of D1R- or D2R-containing neurons in the SNpc and dSTR alleviated behavioral stereotypies of TS, providing a new treatment target for TS. Moreover, the activation of D1R-containing neurons in the dSTR may contribute to the pathogenesis of TS, which can be chosen as a more precise target for treatment.

Highlights

Tourette syndrome (TS) is a common neurobehavioral disorder, the primary symptoms of which include a variety of motor and vocal behavioral stereotypies (Hsu et al, 2021)
We investigated whether chemogenetic activation or inhibition of D1 receptor (D1R)- or D2 receptor (D2R)-containing neurons in the substantia nigra pars compacta (SNpc) or dorsal striatum (dSTR) affected the stereotyped behavior and motor functions of IDPN-induced tourette syndrome (TS) mice, in order to find the neurobiological mechanism of the pathogenesis of TS and choose more precise intervention targets for the treatment of TS
A large number of studies have found that dysfunction of the substantia nigra–striatum network could be the main pathogenesis of TS, which is closely associated with the hyperfunction of the nigrostriatal dopaminergic neurons (Zebardast et al, 2013)

Summary

Introduction

Tourette syndrome (TS) is a common neurobehavioral disorder, the primary symptoms of which include a variety of motor and vocal behavioral stereotypies (Hsu et al, 2021). Male patients have a higher incidence of TS than female patients, and the onset occurs before the age of 18 and lasts for more than 1 year (Ganos and Martino, 2015; Yang et al, 2016). Behavioral stereotypies are defined as rapid, recurrent, and brief movements or vocalizations, the process of which gradually deteriorates (Kawohl et al, 2009). 90% of patients with TS are accompanied by neuropsychiatric diseases, among which attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and impulse control disorder are the most common complications (Ganos and Martino, 2015). It is necessary to investigate the neurobiological mechanisms underlying the pathogenesis of TS and choose more precise intervention targets

Methods

Results

Conclusion