Basal Ganglia Circuits
Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which the loss of substantia nigra pars compacta dopamine neurons leads to cognitive and motor impairments. Motor symptoms include resting tremor, rigidity, altered gait, and bradykinesia. The most effective treatment for PD is dopamine replacement therapy, which is currently the DA precursor, L-dopa. Continued use of this drug, however, results in decreased efficacy and dyskinesias. For these reasons, L-dopa is typically prescribed at later stages in the disease. Treatments that effectively mimic endogenous striatal dopamine without triggering dyskinesias would greatly improve the standard of care for PD.
Studies in our laboratory take advantage our discovery that mice lacking VGLUT3 do not develop motor deficits in a model of Parkinson’s disease. The KO mice show increased synthesis, packaging and release of dopamine in the striatum during their waking cycle, but not during their sleep cycle. The density of immature spines on direct pathway MSNs is also increased only at night. Remarkably, motor function after dopamine depletion is normal not only during the waking cycle when dopamine levels are elevated but throughout the circadian cycle, pointing to a more permanent form of plasticity (Divito et al J. Neurosci, 2015, Brague et al, submitted 2020). Our work further indicates that the transient elevation of dopamine during the induction of PD, preserves the morphology and connectivity of direct pathway (go) medium spiny neurons, likely rebalancing the basal ganglia circuitry to produce normal movement. We are using chemogenetics, slice electrophysiology, 2-photon in vivo calcium imaging, single cell sequencing and functional circuit mapping to better understand the mechanisms that underlie this previously unappreciated form of striatal plasticity and how it impacts basal ganglia function. Ultimately, we would like to apply these findings therapeutically to stave off the debilitating motor symptoms of Parkinson’s disease and to determine if similar mechanisms apply to the co-morbid non-motor symptoms, such as depression and cognitive dysfunction.