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Series GSE40377 Query DataSets for GSE40377
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
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.
Overall design n=4-6 per group. WT mice used as a control for PDE10A KO mice, vehicle control for PDE10A inhibitor treatment.
Contributor(s) Lanz TA, Kleiman RJ
Citation(s) 20923867
Submission date Aug 24, 2012
Last update date Feb 11, 2019
Contact name Thomas A Lanz
Phone 860-686-0546
Organization name Pfizer
Department Neuroscience
Street address Eastern Point Rd MS# 8220-4243
City Groton
State/province CT
ZIP/Postal code 06340
Country USA
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (42)
GSM992480 KO HPC Veh 25
GSM992481 KO HPC Veh 26
GSM992482 KO HPC Veh 28
BioProject PRJNA173797

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Supplementary file Size Download File type/resource
GSE40377_RAW.tar 153.3 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

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