Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A
PDE10A is a member of the phosphodiesterase superfamily highly enriched within medium spiny neurons (MSN) in mammalian striatum. We have used inhibitors of PDE10A and quantitative measures of mRNA to demonstrate that PDE10A controls striatal gene expression by regulating MSN cyclic nucleotide signal...
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| Veröffentlicht in: | Neuropharmacology 2010-02, Vol.58 (2), p.444-451 |
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| creator | Strick, Christine A. James, Larry C. Fox, Carol B. Seeger, Thomas F. Menniti, Frank S. Schmidt, Christopher J. |
| description | PDE10A is a member of the phosphodiesterase superfamily highly enriched within medium spiny neurons (MSN) in mammalian striatum. We have used inhibitors of PDE10A and quantitative measures of mRNA to demonstrate that PDE10A controls striatal gene expression by regulating MSN cyclic nucleotide signaling pathways. Acute treatment with PDE10A inhibitors produces rapid and transient transcription of the immediate early gene cfos in rat striatum. Although inhibition of PDE10A causes accumulation of both cAMP and cGMP, the increase in striatal cfos expression appears to depend on changes in cAMP, since the increase is present in mice deficient in nNOS which fail to increase cGMP in response to PDE10A inhibition. Consistent with its expression in a majority of striatal MSN, PDE10A inhibition significantly induces expression of both substance P and enkephalin, neuropeptide markers for the direct and indirect striatal output pathways, respectively. These findings support the hypothesis that PDE10A modulates signal transduction in both striatal output pathways and suggest that PDE10A inhibitors may offer a unique approach to the treatment of schizophrenia. |
| doi_str_mv | 10.1016/j.neuropharm.2009.09.008 |
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We have used inhibitors of PDE10A and quantitative measures of mRNA to demonstrate that PDE10A controls striatal gene expression by regulating MSN cyclic nucleotide signaling pathways. Acute treatment with PDE10A inhibitors produces rapid and transient transcription of the immediate early gene cfos in rat striatum. Although inhibition of PDE10A causes accumulation of both cAMP and cGMP, the increase in striatal cfos expression appears to depend on changes in cAMP, since the increase is present in mice deficient in nNOS which fail to increase cGMP in response to PDE10A inhibition. Consistent with its expression in a majority of striatal MSN, PDE10A inhibition significantly induces expression of both substance P and enkephalin, neuropeptide markers for the direct and indirect striatal output pathways, respectively. 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James, Larry C. ; Fox, Carol B. ; Seeger, Thomas F. ; Menniti, Frank S. ; Schmidt, Christopher J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c501t-c5e3b5eb17dbef18f4146e6cdf20dd8c9f3f7cd3b0e0fbb1a7b004336b92df1e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>cfos</topic><topic>Corpus Striatum - drug effects</topic><topic>Corpus Striatum - metabolism</topic><topic>Cyclic AMP - genetics</topic><topic>Cyclic AMP - metabolism</topic><topic>Cyclic GMP - genetics</topic><topic>Cyclic GMP - metabolism</topic><topic>Enkephalin</topic><topic>Enkephalins - genetics</topic><topic>Enkephalins - metabolism</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred Strains</topic><topic>Mice, Knockout</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Neurotensin</topic><topic>Nitric Oxide Synthase Type I - genetics</topic><topic>Papaverine - pharmacology</topic><topic>PDE10A</topic><topic>Phosphodiesterase</topic><topic>Phosphodiesterase Inhibitors - pharmacology</topic><topic>Phosphoric Diester Hydrolases - genetics</topic><topic>Phosphoric Diester Hydrolases - metabolism</topic><topic>Proto-Oncogene Proteins c-fos - genetics</topic><topic>Proto-Oncogene Proteins c-fos - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Regulation of striatal gene expression</topic><topic>RNA, Messenger - metabolism</topic><topic>Striatum</topic><topic>Substance P</topic><topic>Substance P - genetics</topic><topic>Substance P - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Strick, Christine A.</creatorcontrib><creatorcontrib>James, Larry C.</creatorcontrib><creatorcontrib>Fox, Carol B.</creatorcontrib><creatorcontrib>Seeger, Thomas F.</creatorcontrib><creatorcontrib>Menniti, Frank S.</creatorcontrib><creatorcontrib>Schmidt, Christopher J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Neuropharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Strick, Christine A.</au><au>James, Larry C.</au><au>Fox, Carol B.</au><au>Seeger, Thomas F.</au><au>Menniti, Frank S.</au><au>Schmidt, Christopher J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A</atitle><jtitle>Neuropharmacology</jtitle><addtitle>Neuropharmacology</addtitle><date>2010-02-01</date><risdate>2010</risdate><volume>58</volume><issue>2</issue><spage>444</spage><epage>451</epage><pages>444-451</pages><issn>0028-3908</issn><eissn>1873-7064</eissn><abstract>PDE10A is a member of the phosphodiesterase superfamily highly enriched within medium spiny neurons (MSN) in mammalian striatum. We have used inhibitors of PDE10A and quantitative measures of mRNA to demonstrate that PDE10A controls striatal gene expression by regulating MSN cyclic nucleotide signaling pathways. Acute treatment with PDE10A inhibitors produces rapid and transient transcription of the immediate early gene cfos in rat striatum. Although inhibition of PDE10A causes accumulation of both cAMP and cGMP, the increase in striatal cfos expression appears to depend on changes in cAMP, since the increase is present in mice deficient in nNOS which fail to increase cGMP in response to PDE10A inhibition. Consistent with its expression in a majority of striatal MSN, PDE10A inhibition significantly induces expression of both substance P and enkephalin, neuropeptide markers for the direct and indirect striatal output pathways, respectively. 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| subjects | Animals cfos Corpus Striatum - drug effects Corpus Striatum - metabolism Cyclic AMP - genetics Cyclic AMP - metabolism Cyclic GMP - genetics Cyclic GMP - metabolism Enkephalin Enkephalins - genetics Enkephalins - metabolism Gene Expression Regulation - drug effects Male Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Knockout Neurons - drug effects Neurons - metabolism Neurotensin Nitric Oxide Synthase Type I - genetics Papaverine - pharmacology PDE10A Phosphodiesterase Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - genetics Phosphoric Diester Hydrolases - metabolism Proto-Oncogene Proteins c-fos - genetics Proto-Oncogene Proteins c-fos - metabolism Rats Rats, Sprague-Dawley Regulation of striatal gene expression RNA, Messenger - metabolism Striatum Substance P Substance P - genetics Substance P - metabolism |
| title | Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A |
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