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.
Studies in our laboratory are focused on the discovery that mice lacking the vesicular glutamate transporter 3, VGLUT3 do not develop motor deficits in a mouse model of Parkinson’s disease (Divito et al J. Neurosci, 2015, Brague et al, bioRxiv 2024). Using DREADDs targeted to midbrain dopamine neurons in wildtype mice, we found that if we elevate the levels of dopamine in the early stages of degeneration, we can induce a form of striatal plasticity that preserves motor function. We are currently performing experiments to understand the mechanisms underlying this form of plasticity with the goal of developing a therapeutic to induce the plasticity and slow the development of motor impairments in PD patients.
Our experiments use 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.