ArrayExpress Uploader06991PDE10A KOhippocampusvehicle controlPDE10A KOhippocampusvehicle controlPDE10A KOhippocampusvehicle controlPDE10A KOhippocampusvehicle controlPDE10A KOhippocampusvehicle controlPDE10A KOhippocampusPDE10iPDE10A KOhippocampusPDE10iPDE10A KOhippocampusPDE10iPDE10A KOhippocampusPDE10iPDE10A KOhippocampusPDE10iWThippocampusvehicle controlWThippocampusvehicle controlWThippocampusvehicle controlWThippocampusvehicle controlWThippocampusvehicle controlWThippocampusvehicle controlWThippocampusPDE10iWThippocampusPDE10iWThippocampusPDE10iWThippocampusPDE10iWThippocampusPDE10iWThippocampusPDE10iPDE10A KOstriatumvehicle controlPDE10A KOstriatumvehicle controlPDE10A KOstriatumvehicle controlPDE10A KOstriatumvehicle controlPDE10A KOstriatumvehicle controlPDE10A KOstriatumPDE10iPDE10A KOstriatumPDE10iPDE10A KOstriatumPDE10iPDE10A KOstriatumPDE10iWTstriatumvehicle controlWTstriatumvehicle controlWTstriatumvehicle controlWTstriatumvehicle controlWTstriatumvehicle controlWTstriatumPDE10iWTstriatumPDE10iWTstriatumPDE10iWTstriatumPDE10iWTstriatumPDE10iWTstriatumPDE10iarrayexpress_sid6Inhibition of phosphodiesterase 10A (PDE10A) promotes cyclic nucleotide signaling, increases striatal activation, and decreases...20923867E-GEOD-40377/profile/8773/arrayexpressuploader342diseasehistonehuntington's diseasenucleotideoutsidestriatumDec.12, 2014Falsemicroarray-profiling-of-wt-or-pde10a-ko-mice-treatE-GEOD-40377_A-AFFY-45Microarray profiling of WT or PDE10A KO mice treated with vehicle or a PDE10 inhibitorNov.12, 2014Inhibition 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. n=4-6 per group. WT mice used as a control for PDE10A KO mice, vehicle control for PDE10A inhibitor treatment.http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-40377mousehttp://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-40377/samples/