EFFECT OF CHEMOGENETIC SUBTHALAMIC NUCLEUS INHIBITION ON MOTOR SYMPTOMS IN A 6-OHDA RAT MODEL OF PARKINSON’S DISEASE AND L-DOPA-INDUCED DYSKINESIA

Objective: Levodopa-induced dyskinesia (LID) significantly limits the long-term management of Parkinson’s Disease (PD). Given the critical role of the subthalamic nucleus (STN) in basal ganglia circuitry, this study aimed to evaluate the efficacy of chemogenetic STN inhibition on LID severity and motor symptoms in a 6-hydroxydopamine (6-OHDA)-induced PD rat model.
Materials and methods: Unilateral PD was induced in adult Sprague-Dawley rats via stereotaxic 6-OHDA injection into the medial forebrain bundle. Experimental groups received intra-STN injections of AAV-hSyn-hM4D(Gi)-mCherry (activated by clozapine N-oxide), while controls received Muscimol (positive control) or a null viral vector. Following model validation, LID was induced via L-DOPA/benserazide administration for 7 days. Efficacy was assessed using the Abnormal Involuntary Movement (AIM) scale, apomorphine-induced rotation, cylinder, and locomotor activity tests.
Results: Apomorphine-induced rotations increased after CNO administration in AAV-mCherry and AAV-M4i groups (p=0.0019 and p=0.0277, respectively), while a significant decrease was observed in the Muscimol group (p=0.0003). Contralateral forelimb use improved across all groups after treatment (AAV-mCherry, p=0.0057; AAV-M4i, p<0.0001; Muscimol, p<0.0001). Regarding dyskinesia, while Muscimol significantly reduced AIM scores (60-160 min), chemogenetic inhibition increased dyskinesia scores, particularly in axial and limb subtypes (p<0.05). Histological verification indicated viral expression but spread to the internal capsule was detected.
Conclusion: Although pharmacological inhibition confirmed the STN's role in modulating motor circuits, the specific chemogenetic Gi-pathway inhibition employed here did not alleviate PD symptoms or LID, likely due to off-target effects and expression sensitivity. These findings highlight the necessity for precise expression optimization in developing chemogenetic therapeutic strategies for PD.