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

被引:26
作者
Meurers, Bernhard H. [1 ,2 ]
Dziewczapolski, Gustavo [3 ,4 ]
Shi, Tao [2 ]
Bittner, Anton [2 ]
Kamme, Fredrik [2 ]
Shults, Clifford W. [3 ,4 ]
机构
[1] Univ Calif Los Angeles, Dept Neurol, David Geffen Sch Med, Los Angeles, CA 90095 USA
[2] Johnson & Johnson Pharmaceut Res & Dev LLC, San Diego, CA 92121 USA
[3] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
[4] Vet Affairs San Diego Healthcare Syst, San Diego, CA 92161 USA
基金
美国国家卫生研究院;
关键词
STRIATAL SYNAPTIC PLASTICITY; NUCLEUS-ACCUMBENS NEURONS; MEDIUM SPINY NEURONS; PARKINSONS-DISEASE; BASAL GANGLIA; MOLECULAR CHARACTERIZATION; MICROARRAY ANALYSIS; INDUCED DYSKINESIA; RAT NEOSTRIATUM; RECEPTOR;
D O I
10.1523/JNEUROSCI.5310-08.2009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 D-1 and D-2 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.
引用
收藏
页码:6828 / 6839
页数:12
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