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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 25, 2012 |
| Title |
Microarray profiling of WT or PDE10A KO mice treated with vehicle or a PDE10 inhibitor |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Inhibition of phosphodiesterase 10A (PDE10A) promotes cyclic nucleotide signaling, increases striatal activation, and decreases behavioral activity. Enhanced cyclic nucleotide signaling is a well established route to producing changes in gene expression. We hypothesized that chronic suppression of PDE10A activity would have significant effects on gene expression in the striatum. A comparison of the expression profile of PDE10A knockout (KO) mice and wild-type mice after chronic PDE10A inhibition revealed altered expression of 19 overlapping genes with few significant changes outside the striatum or after administration of a PDE10A inhibitor to KO animals. Chronic inhibition of PDE10A produced up-regulation of mRNAs encoding genes that included prodynorphin, synaptotagmin10, phosphodiesterase 1C, glutamate decarboxylase 1, and diacylglycerol O-acyltransferase and a down-regulation of mRNAs encoding choline acetyltransferase and Kv1.6, suggesting long-term suppression of the PDE10A enzyme is consistent with altered striatal excitability and potential utility as a antipsychotic therapy. In addition, up-regulation of mRNAs encoding histone 3 (H3) and down-regulation of histone deacetylase 4, follistatin, and claspin mRNAs suggests activation of molecular cascades capable of neuroprotection. We used lentiviral delivery of cAMP response element (CRE)-luciferase reporter constructs into the striatum and live animal imaging of 2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid (TP-10)-induced luciferase activity to further demonstrate PDE10 inhibition results in CRE-mediated transcription. Consistent with potential neuroprotective cascades, we also demonstrate phosphorylation of mitogen- and stress-activated kinase 1 and H3 in vivo after TP-10 treatment. The observed changes in signaling and gene expression are predicted to provide neuroprotective effects in models of Huntington's disease.
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| Overall design |
n=4-6 per group. WT mice used as a control for PDE10A KO mice, vehicle control for PDE10A inhibitor treatment.
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| Contributor(s) |
Lanz TA, Kleiman RJ |
| Citation(s) |
20923867 |
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| Submission date |
Aug 24, 2012 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Thomas A Lanz |
| E-mail(s) |
[email protected]
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| Phone |
860-441-3551
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| Organization name |
Pfizer
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| Department |
Multi-Omics & Biomarkers
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| Street address |
Eastern Point Rd
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| City |
Groton |
| State/province |
CT |
| ZIP/Postal code |
06340 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (42)
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| Relations |
| BioProject |
PRJNA173797 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE40377_RAW.tar |
153.3 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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