Chronic suppression of phosphodiesterase 10A alters striatal expression of genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntington's disease

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 336; no. 1; pp. 64 - 76
• Main Authors: Kleiman, Robin J, Kimmel, Lida H, Bove, Susan E, Lanz, Thomas A, Harms, John F, Romegialli, Alison, Miller, Kenneth S, Willis, Amy, des Etages, Shelley, Kuhn, Max, Schmidt, Christopher J
• Format: Journal Article
• Language: English
• Published: United States 01.01.2011
• Subjects: Animals; Corpus Striatum - drug effects; Corpus Striatum - enzymology; Corpus Striatum - metabolism; Disease Models, Animal; Gene Expression Profiling - methods; Gene Expression Regulation - drug effects; Huntington Disease - drug therapy; Huntington Disease - enzymology; Huntington Disease - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurotransmitter Agents - antagonists & inhibitors; Neurotransmitter Agents - biosynthesis; Neurotransmitter Agents - genetics; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - therapeutic use; Phosphoric Diester Hydrolases - deficiency; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Quinolines - pharmacology; Quinolines - therapeutic use; Signal Transduction - drug effects; Signal Transduction - genetics
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.173294

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.