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The Journal of Neuroscience, May 27, 2009, 29(21):6828-6839; doi:10.1523/JNEUROSCI.5310-08.2009

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Neurobiology of Disease
Dopamine Depletion Induces Distinct Compensatory Gene Expression Changes in DARPP-32 Signal Transduction Cascades of Striatonigral and Striatopallidal Neurons

Bernhard H. Meurers,^1,2 Gustavo Dziewczapolski,^3,4 Tao Shi,² Anton Bittner,² Fredrik Kamme,² and Clifford W. Shults^3,4 

¹Department of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, ²Johnson & Johnson Pharmaceutical Research and Development L.L.C., San Diego, California 92121, ³Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0662, and ⁴Veterans Affairs San Diego Healthcare System, San Diego, California 92161

Correspondence should be addressed to Bernhard H. Meurers, Department of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095. Email: bmeurers{at}ljmail.net

Functional alterations in striatal projection neurons play a critical role in the development of motor symptoms in Parkinson's disease (PD), but their molecular adaptation to dopamine depletion remains poorly understood. In particular, type and extent of regulation in postsynaptic signal transduction pathways that determine the responsiveness of striatal projection neurons to incoming stimuli, are currently unknown. Using cell-type-specific transcriptome analyses in a rodent model of chronic dopamine depletion, we identified large-scale gene expression changes, including neurotransmitter receptors, signal transduction cascades, and target proteins of dopamine signaling in striatonigral and striatopallidal neurons. Within the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) cascade of enzymes that plays a central role in signal integration of dopaminoceptive neurons multiple catalytic and regulatory subunits change their mRNA expression levels. In addition to the number of genes the fact that the alterations occur at multiple levels stresses the biological relevance of transcriptional regulation for adaptations of postsynaptic signaling pathways. The overall pattern of changes in both striatonigral and striatopallidal neurons is compatible with homeostatic mechanisms. In accordance with the distinct biological effects of dopamine D₁ and D₂ receptor stimulation, the alterations of the transcriptional profiles most likely result in prodopaminergic phosphorylation patterns. Our data provide insight into the disease-related plasticity of functional genomic networks in vivo that might contribute to the protracted preclinical phase of PD. In addition, the data have potential implications for the symptomatic treatment of the disease.

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Received Nov. 4, 2008; revised March 22, 2009; accepted March 24, 2009.

Correspondence should be addressed to Bernhard H. Meurers, Department of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095. Email: bmeurers{at}ljmail.net

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