Ying Xu,1,2 Li-Na Li,1,2,* Xiang-Jun He,1,2 Shuang Wang,2 Xincheng Li,2 Hao Feng,2 Hui-Feng Zhang,1 Li Song,2 Hai-Shui Shi,2– 4,* Xiao-Yu Tian1,* 

1The Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China; 2Neuroscience Research Center, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; 3Nursing School, Hebei Medical University, Shijiazhuang, 050031, People’s Republic of China; 4Hebei Key laboratory of Neurophysiology, Hebei Medicinal University, Shijiazhuang, 050017, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xiao-Yu Tian, The Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China, Email janetian@hebmu.edu.cn

Context: Tourette syndrome (TS) is a common chronic neuropsychiatric disorder with a prevalence of approximately 1% in children and adolescents. TS is characterized by sudden involuntary motor tics along with vocal tics. A pathological study on postmortem patients has reported a 50– 60% reduction in striatal gamma-aminobutyric acidergic (GABAergic) interneurons, suggesting a role for GABAergic system imbalances in tic disorder development. However, the effect of exogenous GABA administration on tic alleviation remains unreported.
Objective: In this study, we aim to investigate the therapeutic effects of exogenous GABA on TS-like behaviors in Sprague-Dawley rats and explore its potential mechanisms, including gut microbiota regulation, oxidative stress mitigation, and restoration of GABA-glutamate balance, to provide insights into TS pathogenesis and alternative treatment strategies.
Materials and Methods: A TS model rat was established through intraperitoneal administration of 3,3-Iminodipropionitrile (150 mg/kg/day), followed by GABA (20 mg/kg/day) administration by gavage. 15 minutes of behavioral testing (stereotypical behavior and head twitching behavior) was then conducted. 16S rRNA sequencing identified microbiome changes, and LC-MS assessed striatal metabolite changes.
Results: The results showed that a 4-week GABA treatment alleviated TS-like behavior in rats. GABA treatment led to an increase in Acinetobacter and other beneficial bacteria. GABA also significantly upregulated 15 striatal metabolites compared with TS group. By correlation analysis of striatal metabolites and intestinal bacteria, statistical analysis showed that Clostridium_sensu_stricto_1 was negatively correlated with metabolites on the top 20 differential gut microbiota and metabolites. Moreover, changes in gut microbiota correlated with alterations in striatal metabolites, suggesting a gut-brain axis involvement.
Conclusion: Exogenous GABA alleviated TS-like behavior in rats by reducing harmful gut flora and modulating striatal GABA-glutamate metabolism. Despite challenges like low blood-brain barrier permeability and dose safety in humans, GABA’s therapeutic potential may be realized through prodrug development and optimized dosing. These findings are preliminary and require further clinical validation.

Keywords: Tourette syndrome, GABA, gut microbiota, striatum metabolism