2026 American Academy of Neurology Abstract Website

Objective:

To determine whether neuronal deletion of cannabinoid receptor 2 (CB2R) in NeuroD6-positive neurons reduces the frequency and severity of levodopa-induced dyskinesia (LID) in a Parkinson’s disease (PD) mouse model.

Background:

PD is defined by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). While levodopa remains the cornerstone of PD treatment, chronic use often causes LID, characterized by involuntary, hyperkinetic movements driven by pulsatile dopamine levels that alter cortico-basal ganglia activity. CB2R is implicated in neuroinflammation, yet its contribution to LID remains unclear. Preliminary work suggests that neuronal, rather than microglial, CB2R deletion influences dysregulation underlying LID.

Design/Methods:

Unilateral 6-hydroxydopamine (6-OHDA) or ascorbic acid (Sham) was injected into the dorsomedial striatum of mice to replicate dopaminergic neuron loss in PD. Dopaminergic cell loss was confirmed by tyrosine hydroxylase (TH) immunofluorescence in the SNpc. Motor deficits were assessed using behavioral assays (balance beam, pole, and cylinder tests). Experiments were performed in mice with CB2R deletion in NeuroD6-positive neurons (NEX^Cre/+CB2^EGFP/f/f/) and their controls (NEX^Cre/+). Following confirmation of PD-like pathology and motor impairment, LID was generated by daily levodopa/benserazide intraperitoneal injections for three weeks in 6-OHDA mice for both genotypes. The rodent Abnormal Involuntary Movement (AIM) scale was used to score dyskinesia frequency and severity.

Results:

Immunofluorescence exhibited significant loss of TH+ neurons in the 6-OHDA lesioned hemisphere compared to Sham mice (p<0.05). Behavioral assays revealed that, regardless of genotype, 6-OHDA mice exhibited worse overall motor deficits compared to Sham mice (p<0.001), thus confirming presence of PD-like symptoms. Lastly, evaluation of AIMs in 6-OHDA treated NEX^Cre/+CB2^EGFP/f/f/ versus NEX^Cre/+ mice indicated CB2R deletion resulted in lower overall LID score compared to controls (46.14 vs 59.83, p=0.26).

Conclusions:

Neuronal CB2R deletion mitigated AIMs, suggesting it may play a role in modulating LID in PD mouse model; however, larger sample sizes are needed to validate findings.