Striatal Delta FosB gene suppression inhibits the development of abnormal involuntary movements induced by L-Dopa in rats

L-Dopa-induced dyskinesia (LID) is associated with the upregulation of striatal increment FosB in animal models and patients with Parkinson's disease (PD). A mechanistic role of increment FosB is suspected because its transgenic overexpression leads to the early appearance of LID in rodents and primates. This study in rodents is aimed at exploring the therapeutic potential of striatal increment FosB gene suppression to control LID in patients with PD. To determine the effect of reducing striatal increment FosB expression, we used RNAi gene knockdown in a rat model of PD and assessed abnormal involuntary movements (AIMs) in response to L-Dopa. Rats with dopamine depletion received striatal injections of rAAV- increment FosB shRNA or a control virus before exposure to chronic L-Dopa treatment. The development of AIMs during the entire L-Dopa treatment period was markedly inhibited by increment FosB gene knockdown and its associated molecular changes. The antiparkinsonian action of L-Dopa was unchanged by increment FosB gene knockdown. These results suggest a major role for increment FosB in the development of LID and support exploring strategies to reduce striatal increment FosB levels in patients with PD.