Pivotal Role of Slitrk1 in Adult Striatal Cholinergic Neurons in Mice: Implication in Tourette Syndrome

Abstract

ObjectiveThe 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.MethodsSlitrk1‐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.ResultsSlitrk1‐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.InterpretationSlitrk1 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 2024;95:174–189