Parkinson's disease (PD) causes disability in an estimated 1 million Americans and is characterized by progressive loss of dopaminergic neurons that originate in the substantia nigra pars compacta (SNpc) and their axons. Levodopa (LD) in some form is required to control symptoms of PD in vast majority of patients, but its use causes drug-induced dyskinesias (DID), motor and non motor fluctuations, disabling complications that remains a major problem in contemporary management of PD. Intermittent high dose LD treatments, loss of continuous dopaminergic stimulation (CDS) along with dopamine receptor super sensitivity are hypothesized as causative factors for DID and fluctuations. It is also well accepted that information transfer from the motor cortex to the basal ganglia and back is abnormal in PD and correction of electrophysiological abnormalities may be critical to provide symptomatic relief to patients with advanced PD. Our studies show that the electrophysiological changes that occur in the basal ganglia as result of parkinsonism remain largely unmitigated with round the clock LD treatments despite excellent amelioration of parkinsonian behavior. In contrast, dopaminergic cell transplants into the striatum ?normalize? basal ganglia neurophysiology and parkinsonian behavioral abnormalities. We show that synaptic connectivity between the graft and the host is critical and necessary to mediate these effects. These findings suggest that pre-synaptic factors such as the presence of nigrostriatal synapses that enables focused release of dopamine, its reuptake and regulation via pre-synaptic receptors may all be important to minimize the motor complications of PD. Recent studies have shown that dopaminergic cell transplantation for PD can be successful and without deleterious side effects providing >2 decades of effective anti-parkinsonian benefits to patients. This has led to the lifting of the moratorium on clinical cell transplantation for PD. However, optimization of cell transplantation techniques including the ability to externally control the functioning of the grafts and its newly formed synaptic connections with the host is critical to ensure safety of future clinical translation of such grafts. Therefore, we seek to comprehensively evaluate the hypothesis that electrophysiological ?normalization? in the basal ganglia ? cortical circuit is necessary to mitigate or eliminate DID and fluctuations in PD. Using a highly reproducible rat model of PD that exhibit DID and fluctuations, optogenetic and chemogenetic modulation of grafts such that they can be turned ?off? and ?on?, awake basal ganglia single cell recordings, LFP recordings, EEG and in vivo microdialysis combined with HPLC-Ms/Ms we plan to study the biochemical and electrical abnormalities in the basal ganglia and the cortex associated with DID and fluctuations in PD. Multiple nuclei in the basal ganglia and its known connections will be probed. Extensive histological studies will also be performed. This research will provide mechanistic basis for the electrophysiological abnormalities that accompany DID, motor and non- motor fluctuations in PD and help discover methods to correct them.
This grant renewal application seeks to evaluate the cause of serious complications of medical treatments for Parkinson's disease, a disease that afflicts over 1 million Americans. Understanding these causes will lead to us avoiding such complications and improving treatments.