Pivotal role of Slitrk1 in adult striatal cholinergic neurons in mice: Implication in Tourette syndrome.

Abstract

The SLIT and NTRK-like 1 (SLITRK1) gene mutation and striatal cholinergic interneurons (ChIs) loss are associated with Tourette syndrome (TS). ChIs comprise only 1-2% of total neurons but send dense arbors of fibers in the stratum, making it the most ACh-abundant brain region. Here, mice receiving Slitrk1 siRNA bilateral microinjection in the dorsal striatum, Slitrk1-knockdown (KD) mice, exhibit TS-like haloperidol-sensitive stereotypic tic behaviors and impaired prepulse inhibition, as well as delayed sensorimotor response, compared with scrambled siRNA-treated controls. 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. These results suggest that 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. This article is protected by copyright. All rights reserved.