A model of L-DOPA-induced dyskinesia in parkinsonian mice produced by AAV vector-mediated overexpression of α-synuclein

Abstract

L-3,4-dihydroxyphenylalanin (L-DOPA) is the most effective drug for treating Parkinson's disease (PD); however, long-term L-DOPA therapy can lead to L-DOPA-induced dyskinesia (LID). While the 6-hydroxydopamine-lesioned rodent model for LID fails to reproduce the pathological hallmarks of PD, a newly introduced rodent model using adeno-associated virus (AAV)-mediated overexpression of α-synuclein results in α-synuclein aggregation and progressive loss of dopaminergic neurons. The present study aimed to provoke LID in parkinsonian mice generated by AAV vector-mediated overexpression of α-synuclein and to explore histologic features associated with LID. A recombinant AAV2/7 vector containing the human α-synuclein transgene was injected into the substantia nigra (SN) of wild-type mice. Eight weeks later, mice received daily injections of 10 mg/kg of L-DOPA for one week, followed by 25 mg/kg of L-DOPA daily for the subsequent week. LID was observed in 3 out of 19 mice at the 10 mg/kg L-DOPA dose and in 14 mice at 25 mg/kg dose. The number of tyrosine hydroxylase (TH)-positive neurons in the AAV vector-injected side of the SN was reduced to an average of 59 % of the intact side, and the optical density of TH-positive fibers in the ipsilateral striatum was reduced to an average of 37 %. Abnormal Involuntary Movement scores were correlated with decrease in both the number of TH-positive neurons in SN and optical density of striatal TH-positive fibers. This study establishes a mouse model for LID using AAV vector-mediated overexpression of α-synuclein, providing a useful tool for investigating the progressive changes and associated pathophysiology during occurrence of LID.