In Parkinson's disease (PD), dopamine replacement therapies work well for the first a few years. However, in late stage PD, such therapies cause dyskinesia that is often more debilitating than PD itself. There is an urgent need to develop alternative approaches to treat motor impairment. We recently found that mice deficient for the striatum enriched adenylyl cyclase (AC) type V (AC5) display dopamine D2 receptor- independent motor control. However they are still dependent on dopamine D1 receptors. We hypothesize that over-expression of adenylyl cyclase type I (AC1) in striatal D1 receptor positive neurons will enable D1 receptor-independent motor control. We further hypothesize that double transgenic mice with both AC1 over-expression in D1 neurons and AC5 deficiency will display dopamine-independent motor control. We propose to generate these transgenic mice and test our hypotheses using dopamine antagonists, dopamine depletion and dopamine neuron lesions. We will examine motor functions using locomotor activity, akinesia test, gait analysis and rotarod.

Public Health Relevance

We will generate transgenic mice with dopamine-independent motor control. Positive results will provide proof of principle and will guide the development of non- dopamine replacement based therapies for Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS070269-02
Application #
8016625
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sieber, Beth-Anne
Project Start
2010-02-01
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
2
Fiscal Year
2011
Total Cost
$224,052
Indirect Cost
Name
University of Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Koranda, Jessica L; Cone, Jackson J; McGehee, Daniel S et al. (2014) Nicotinic receptors regulate the dynamic range of dopamine release in vivo. J Neurophysiol 111:103-11
Zhuang, Xiaoxi; Mazzoni, Pietro; Kang, Un Jung (2013) The role of neuroplasticity in dopaminergic therapy for Parkinson disease. Nat Rev Neurol 9:248-56
Beeler, Jeff A; Frank, Michael J; McDaid, John et al. (2012) A role for dopamine-mediated learning in the pathophysiology and treatment of Parkinson's disease. Cell Rep 2:1747-61