Becoming bilingual through transmitter co-release

Parkinsons (PD) and Huntingtons disease (HD) are severe neurodegenerative movement disorders with limited treatment options and no disease-modifying therapies. The decline of substantia nigra dopamine (DA) neurons is a major pathological hallmark of PD and results in slowness of movement due to altered GABA signalling in the striatum, which is the input nucleus of the basal ganglia. In contrast, loss of specific sets of GABA neurons in the striatum and subsequent overactivation of other GABA neurons causes the characteristic increases in motor activities of patients with HD. Thus, basal ganglia are differentially affected in PD and HD, but both disorders share dysregulated GABA signalling in the striatum causing either excess activation or inhibition of movement. Can we counteract the overall excess inhibitory GABAergic tones seen in PD and HD? Using mouse models, viral vectors, slice electrophysiology, behavioral assays and histology we will test whether we can modify GABA overactivation in specific nuclei within the striatum through alteration of GABA release and signalling. Our main goal is to further our understanding of selective vulnerability and neurodegeneration seen in PD and HD, and to test whether modifying gene therapies may alleviate these debilitating pathologies.