L-DOPA-induced dyskinesia in a mouse model for Parkinson’s disease produced by AAV vector-mediated overexpression of alpha-synuclein in midbrain dopaminergic neurons

Abstract

L-3,4-dihydroxyphenylalanin (L-DOPA) is the most effective drug in Parkinson’s disease (PD), but long-term L-DOPA therapy leads to an abnormal involuntary movements termed L-DOPA-induced dyskinesia (LID). Rodent model induced by 6-hydroxydopamine (6-OHDA) was used for studies for LID, however it failed to reproduce the pathological hallmarks of PD. A new rodent model using adeno-associated virus (AAV) vector-mediated overexpression of alpha-synuclein was introduced and it displayed alpha-synuclein aggregation and progressive loss of dopaminergic neuron. The purpose of present study is to provoke LID in parkinsonian mice produced by AAV vector-mediated overexpression of alpha-synuclein and to explore histologic features in dopaminergic and serotonergic neuronal activities. C57BL/6 mice were injected with AAV2/7 vector including human alpha-synuclein transgene in substantia nigra. Eight weeks later, 10mg/kg of L-DOPA was injected daily for 7 days and 25mg/kg of L-DOPA was injected for following 7 days. Abnormal Involuntary Movements (AIM) scores were rated for limb, axial, locomotive, and orolingual movements. The immunohistochemistry analyzed dopaminergic neuron loss in substantia nigra and degeneration of striatal dopaminergic and serotonergic fibers. LID was observed in two out of eleven mice at a daily dose of 10mg/kg L-DOPA and in all eleven mice at a daily dose of 25mg/kg L-DOPA. Tyrosine hydroxylase (TH)-positive nigral neuron in AAV vector-injected side was reduced by 25 to 70% of intact side, and optical density of striatal TH-positive fibers was reduced by 60 to 80%. The AIM scores were correlated with both TH-positive nigral neuron loss and optical density of striatal TH-positive fibers. Optical density of striatal serotonin transporter-positive fibers did not change. This study proved LID is produced in alpha-synuclein overexpressed mouse model. The results suggest that the role of dopaminergic and serotonergic activity in LID may differ between alpha-synuclein overexpressed and 6-OHDA-induced models.