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.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Schools of Medicine
United States
Zip Code
Plotkin, Joshua L; Day, Michelle; Peterson, Jayms D et al. (2014) Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease. Neuron 83:178-88
Surmeier, D James; Graves, Steven M; Shen, Weixing (2014) Dopaminergic modulation of striatal networks in health and Parkinson's disease. Curr Opin Neurobiol 29:109-17
Fieblinger, Tim; Graves, Steven M; Sebel, Luke E et al. (2014) Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia. Nat Commun 5:5316
Tan, Chan Lek; Plotkin, Joshua L; Veno, Morten T et al. (2013) MicroRNA-128 governs neuronal excitability and motor behavior in mice. Science 342:1254-8
Plotkin, Joshua L; Shen, Weixing; Rafalovich, Igor et al. (2013) Regulation of dendritic calcium release in striatal spiny projection neurons. J Neurophysiol 110:2325-36
Kress, Geraldine J; Yamawaki, Naoki; Wokosin, David L et al. (2013) Convergent cortical innervation of striatal projection neurons. Nat Neurosci 16:665-7
Glajch, Kelly E; Fleming, Sheila M; Surmeier, D James et al. (2012) Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson's disease. Behav Brain Res 230:309-16
Plotkin, Joshua L; Day, Michelle; Surmeier, D James (2011) Synaptically driven state transitions in distal dendrites of striatal spiny neurons. Nat Neurosci 14:881-8
Ding, Jun B; Guzman, Jaime N; Peterson, Jayms D et al. (2010) Thalamic gating of corticostriatal signaling by cholinergic interneurons. Neuron 67:294-307
Bateup, Helen S; Santini, Emanuela; Shen, Weixing et al. (2010) Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc Natl Acad Sci U S A 107:14845-50

Showing the most recent 10 out of 59 publications