Parkinson's disease (PD) is the second most common neurodegenerative disease of aging. The cardinal motor symptoms of the disease - bradykinesia, rigidity and tremor - are largely the consequence of degeneration of mesencephalic dopaminergic neurons that innervate the striatum. Enhancing the release of dopamine (DA) by increasing the availability of its precursor (levodopa) has been the gold-standard symptomatic treatment for nearly half a century. Although potent initially, in the later stages of the disease as the dosage needed to achieve symptomatic benefit rises, levodopa treatment is plagued by the induction of dyskinesias, so-called levodopa-induced dyskinesia (LID). Emerging evidence points to the importance of striatal interneurons and intrastriatal microcircuits in the pathophysiology of PD and LID. One microcircuit that appears to be particularly important but about which relatively little is known is anchored by GABAergic plateau and low threshold spike interneurons (PLTSIs). Initial studies by our group suggest that PLTSIs are integral elements of a striatal microcircuit that dampens SPN excitability and glutamatergic synaptic strength in response to cortical excitation. It is our over-arching hypothesis that the ability of this homeostatic microcircuit to moderate striatal activity becomes impaired in PD and LID, leading to pathological adaptations in the striatal network and aberrant activity patterns underlying symptoms. The pursuit of this over-arching hypothesis is broken down into four specific aims: 1) to characterize the role of PLTSIs in regulating the dendritic excitability of SPNs; 2) to characterize the role of PLTSIs in regulating glutamatergic synaptic plasticity; 3) to characterize the role of PLTSIs in regulating excitability and synaptic plasticity in SPNs in a mouse model of PD; and 4) to characterize the consequences of LID induction on PLTSI regulation of SPN activity. These four aims will be rigorously pursued using a combination of cutting-edge approaches that overcome the experimental obstacles that have impeded progress to date. These approaches include intersectional pharmacogenomics, optogenetics, two photon laser scanning microscopy, viral gene delivery and electrophysiology in ex vivo brain slices from adult mouse models of disease. The successful achievement of these aims will significantly advance our understanding of the mechanisms underlying PD and LIDs and in so doing promote the development of new therapies for PD patients.
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