Targeting adenylyl cyclase to prevent L-DOPA-induced dyskinesia

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DESCRIPTION (provided by applicant): L-DOPA-induced dyskinesia (LID) in Parkinson's isease (PD) is due to aberrant corticostriatal plasticity. However, how chronic L-DOPA treatment in advanced stage PD causes such aberrant plasticity remains unknown. We focus on the hypothesis that it is the regulated phasic dopamine release that modifies corticostriatal synaptic strength. In advanced stage PD, L-DOPA is able to restore tonic dopamine but not regulated phasic dopamine release from dopamine neurons due to the loss of dopamine terminals in the striatum. Instead, unregulated fluctuations in dopamine release due to L-DOPA therapy will cause aberrant modification of corticostriatal synaptic strength and LID. cAMP pathway is important for corticostriatal plasticity. The main adenylyl cyclase (AC) isoform in the striatum is the calcium-calmodulin (CaCaM)- insensitive isoform AC5. Accordingly, cAMP production in adult striatum relies on G protein coupled receptors. Such a lack of CaCaM stimulation of cAMP production and its reliance on G protein coupled receptor activation makes corticostriatal neuroplasticity dependent on dopamine input. We have generated transgenic mice that express the CaCaM-dependent AC1 in striatal neurons. We hypothesize that in these mice, cAMP pathway in striatal neurons will be activated through CaCaM and NMDA receptor activation from cortical glutamatergic input independent of dopamine input. In advanced stage PD patients who have already lost most of regulated phasic dopamine release and wide fluctuations of dopamine levels contribute to aberrant plasticity, attenuation of dopamine influence on the aberrant plasticity will blunt the effect of dopamine on dyskinesia. The proposed studies aim to provide proof of principle for its potential therapeutic effects on LID. PUBLIC HEALTH RELEVANCE: L-DOPA-induced dyskinesia is a main problem in arkinson's disease therapy. We will test that adenylyl cyclase is a valid target for modifying corticostriatal plasticity and preventing L-DOPA induced dyskinesia.