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

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 P...

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Published inThe 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
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LanguageEnglish
Published United States 01.01.2011
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Abstract 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.
AbstractList 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.
Author Willis, Amy
Lanz, Thomas A
Harms, John F
Miller, Kenneth S
des Etages, Shelley
Kleiman, Robin J
Bove, Susan E
Schmidt, Christopher J
Kimmel, Lida H
Romegialli, Alison
Kuhn, Max
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  givenname: Robin J
  surname: Kleiman
  fullname: Kleiman, Robin J
  email: robin.j.kleiman@pfizer.com
  organization: Neuroscience Research Unit, Eastern Point Road, Pfizer Global Research and Development, Groton, CT 06379, USA. robin.j.kleiman@pfizer.com
– sequence: 2
  givenname: Lida H
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/20923867$$D View this record in MEDLINE/PubMed
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Snippet Inhibition of phosphodiesterase 10A (PDE10A) promotes cyclic nucleotide signaling, increases striatal activation, and decreases behavioral activity. Enhanced...
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StartPage 64
SubjectTerms 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
Title Chronic suppression of phosphodiesterase 10A alters striatal expression of genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntington's disease
URI https://www.ncbi.nlm.nih.gov/pubmed/20923867
https://search.proquest.com/docview/818642542
Volume 336
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