L-DOPA-induced dyskinesias (LID) are common and significant complications of dopaminergic therapy for the treatment of Parkinson's disease (PD). LID arises from complex compensatory changes throughout the basal ganglia, including to the substantia nigra pars reticulata (SNr), a primary output structure. The loss of dopamine (DA) in PD is thought to increase SNr activity, which would inhibit motor thalamus output. Additionally, DA loss causes changes in neuronal firing patterns, including increased burst firing and oscillatory and synchronous activity, in nearly all basal ganglia nuclei; whether changes in firing rate or firing pattern serve as the neurological substrate for PD symptoms or LID expression remains highly debated. To address firing rate, we directly modulated SNr activity with chemogenetics in a unilateral 6-OHDA lesion PD-LID mouse model and found that akinesia was improved by either increasing or decreasing SNr firing rate. By contrast, LID was inhibited by increasing SNr firing, while decreasing the SNr firing rate exacerbated LID from threshold doses of L-DOPA. These data indicate akinesia and LID are mediated dissociable aspects of SNr activity and lead us to propose that akinesia is improved by disrupting firing patterns in the SNr, supporting the abnormal firing pattern model. By contrast, LID is inhibited by counteracting the decrease in SNr firing rate after doses of L-DOPA, supporting the firing rate model. Using the same approach, we directly increased the firing rate of the parafascicular nucleus (Pf), a target of the GABAergic output of the SNr. This also blocked LID expression, suggesting that increasing SNr activity could block dyskinesia by paradoxically increasing Pf firing. However, the activity of SNr neurons and the effect of SNr activity on thalamic targets has not been measured in awake, behaving animals during LID. In this proposal, we will 1) characterize the activity of the SNr and its thalamic targets in awake, behaving animals during states of DA depletion and LID expression; 2) define the connectivity and effect of direct modulation of SNr firing (conditions that alter akinesia and LID) on the activity of SNr target thalamic nuclei (parafascicular, ventrolateral, and reticular thalamic nuclei); and 3) determine the thalamic nuclei at which GABA release from SNr terminals is sufficient to block LID. As LIDs are major limiting factors for symptomatic control of PD, completion of this project and the successful elucidation of the pathological processes that underlie LID expression would advance the development of rationally targeted therapies that extend the efficacy of current drugs and potentially improve the quality of life of those with PD.
L-DOPA-induced dyskinesias (LID) are abnormal involuntary movements that manifest in Parkinson's disease patients after prolonged treatment with L-DOPA, which significantly limits the effectiveness of the drug. The neurological cause of LID is unknown, but involves different types of abnormal neuronal activity in the regions of the brain important for regulating movement. This proposal uses mouse models of LID to define the types of abnormal neuronal activity necessary to cause LID in order to develop therapeutic approaches that counteract them to suppress or prevent the LID.
