Du Jung-Chieh, Chang Man-Hsin, Yeh Chen-Jiun, Lee Ming Tatt, Lee Hsin-Jung, Chuang Shu-Hui, Chiou Lih-Chu
Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Pediatrics, Taipei City Hospital, Zhongxiao Branch, Taipei, Taiwan.
Ann Neurol. 2023 Sep 30. doi: 10.1002/ana.26805.
The SLIT and NTRK-like 1 (SLITRK1) gene mutation and striatal cholinergic interneurons (ChIs) loss are associated with Tourette syndrome (TS). ChIs comprise only 1 to 2% of striatal neurons but project widely throughout the stratum to impact various striatal neurotransmission, including TS-related dopaminergic transmission. Here, we link striatal Slitrk1, ChI function, and dopaminergic transmission and their associations with TS-like tic behaviors.
Slitrk1-KD mice were induced by bilaterally injecting Slitrk1 siRNA into their dorsal striatum. Control mice received scrambled siRNA injection. Their TS-like tic behaviors, prepulse inhibition, sensory-motor function and dopamine-related behaviors were compared. We also compared dopamine and ACh levels in microdialysates, Slitrk protein and dopamine transporter levels, and numbers of Slitrk-positive ChIs and activated ChIs in the striatum between two mouse groups, and electrophysiological properties between Slitrk-positive and Slitrk-negative striatal ChIs.
Slitrk1-KD mice exhibit TS-like haloperidol-sensitive stereotypic tic behaviors, impaired prepulse inhibition, and delayed sensorimotor response compared with the control group. These TS-like characteristics correlate with lower striatal Slitrk1 protein levels, fewer Slitrk1-containing ChIs, and fewer activated ChIs in Slitrk1-KD mice. Based on their electrophysiological properties, Slitrk1-negative ChIs are less excitable than Slitrk1-positive ChIs. Slitrk1-KD mice have lower evoked acetylcholine and dopamine levels, higher tonic dopamine levels, and downregulated dopamine transporters in the striatum, increased apomorphine-induced climbing behaviors, and impaired methamphetamine-induced hyperlocomotion compared with controls.
Slitrk1 is pivotal in maintaining striatal ChIs activity and subsequent dopaminergic transmission for normal motor functioning. Furthermore, conditional striatal Slitrk1-KD mice may serve as a translational modality with aspects of TS phenomenology. ANN NEUROL 2023.
SLIT和NTRK样蛋白1（SLITRK1）基因突变以及纹状体胆碱能中间神经元（ChIs）缺失与抽动秽语综合征（TS）相关。ChIs仅占纹状体神经元的1%至2%，但其广泛投射至纹状体各层，影响包括与TS相关的多巴胺能传递在内的多种纹状体神经传递。在此，我们将纹状体Slitrk1、ChI功能、多巴胺能传递及其与类TS抽动行为的关联联系起来。
通过双侧向背侧纹状体注射Slitrk1小干扰RNA（siRNA）诱导Slitrk1基因敲低（KD）小鼠。对照小鼠接受乱序siRNA注射。比较它们的类TS抽动行为、前脉冲抑制、感觉运动功能和多巴胺相关行为。我们还比较了两组小鼠纹状体微透析液中的多巴胺和乙酰胆碱水平、Slitrk蛋白和多巴胺转运体水平、Slitrk阳性ChIs和活化ChIs的数量，以及Slitrk阳性和Slitrk阴性纹状体ChIs之间的电生理特性。
与对照组相比，Slitrk1-KD小鼠表现出对氟哌啶醇敏感的类TS刻板抽动行为、前脉冲抑制受损以及感觉运动反应延迟。这些类TS特征与Slitrk1-KD小鼠纹状体中较低的Slitrk1蛋白水平、含Slitrk1的ChIs数量减少以及活化ChIs数量减少相关。基于其电生理特性，Slitrk1阴性ChIs的兴奋性低于Slitrk1阳性ChIs。与对照组相比，Slitrk1-KD小鼠纹状体中诱发的乙酰胆碱和多巴胺水平较低、紧张性多巴胺水平较高、多巴胺转运体下调、阿扑吗啡诱导的攀爬行为增加以及甲基苯丙胺诱导的运动亢进受损。
Slitrk1对于维持纹状体ChIs活性以及随后的多巴胺能传递以实现正常运动功能至关重要。此外，条件性纹状体Slitrk1-KD小鼠可能作为具有TS现象学特征的转化模型。《神经病学年鉴》2023年
