Optogenetic Inhibition of Striatal Parvalbuminergic Interneurons Unmasks Impaired GABA and Adenosine Signaling in DYT1 Knock-In Mice

Neurochemical imbalances in the striatum are thought to contribute to the patho-physiology of DYT1 dystonia (TOR1A), a severe movement disorder. Parvalbumin- positive GABAergic fast-spiking interneurons (PV+ FSI) exert a powerful inhibition within the striatal microcircuitry. To elucidate the impact of PV+ FSI on striatal neu-rotransmitter dynamics in a DYT1 knock-in (KI) mouse model, we combined optoge-netic inhibition of PV+ FSI with in vivo microdialysis (optodialysis) and LC-MS/MS analysis. Dialysates were collected across baseline (light off), stimulation (light on, 595 nm) and post-stimulation (light off) periods. Basal extracellular concentrations of sev-eral analytes, including GABA, dopamine and adenosine, showed no significant dif-ferences between wildtype (WT) and DYT1 KI mice. In WT mice, PV+ FSI inhibition decreased GABA and adenosine levels. In contrast, DYT1 KI mice showed no change in GABA and only a delayed reduction in adenosine post-stimulation. Dopamine, choline or 5-HIAA were largely unaffected by optogenetic inhibition, with the exception of a genotype-specific reduction of 5-HIAA in the post-stimulation period. These findings suggest impaired inhibitory and neuromodulatory control in the DYT1 KI mice, po-tentially reflecting compensatory circuit adaptations. The results provide novel insights into striatal microcircuit function in DYT1 dystonia, establish a basis for exploring circuit-level alterations in other movement disorders, and may inform future thera-peutic strategies.