Developmental co‐regulation of the β and γ GABAA receptor subunits with distinct α subunits in the human dorsolateral prefrontal cortex
The GABAA receptor (GABAAR) is a pentameric chloride ion channel that mediates neuronal inhibition and is commonly comprised of 2α, 2β and 1γ subunits. These subunits have distinct characteristics that critically impact receptor function. In this study, we sought to determine if developmental expres...
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description | The GABAA receptor (GABAAR) is a pentameric chloride ion channel that mediates neuronal inhibition and is commonly comprised of 2α, 2β and 1γ subunits. These subunits have distinct characteristics that critically impact receptor function. In this study, we sought to determine if developmental expression of the β and γ subunit mRNAs in the prefrontal cortex would show complementary or opposing patterns of change as compared to the α subunits. Certain GABAAR subunit genes are arranged in tandem on the chromosome, and we hypothesized that genomic proximity would lead to co‐regulation during development.
The mRNA expression of the 3β and 3γ subunits was measured in the human dorsolateral prefrontal cortex of 68 individuals aged neonate to adult, using microarray with qPCR validation. Changes between age groups were identified through ANOVA, linear regression and post hoc Fisher LSD tests while a principal component analysis was used to establish co‐regulation of GABAAR genes.
β1, γ1 and γ3 subunits decreased in expression with age whereas γ2 increased. β2 showed dynamic regulation with early increases plateauing across childhood and adolescence before decreasing in adulthood while β3 levels remained relatively constant. Using published α subunit data we identified two principal components labeled ‘Decreasing’ (α2, α5, β1, γ1 and γ3) and ‘Dynamic’ (α1, α4, β2 and γ2) responsible for 84% of the variation in GABAAR subunit development.
This grouping is generally consistent with the chromosomal localization of subunits, lending credence to regional transcriptional control mechanisms. In addition, understanding developmental changes in GABAAR subunits could foster better pediatric pharmaceutical treatments. |
doi_str_mv | 10.1016/j.ijdevneu.2010.05.004 |
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The mRNA expression of the 3β and 3γ subunits was measured in the human dorsolateral prefrontal cortex of 68 individuals aged neonate to adult, using microarray with qPCR validation. Changes between age groups were identified through ANOVA, linear regression and post hoc Fisher LSD tests while a principal component analysis was used to establish co‐regulation of GABAAR genes.
β1, γ1 and γ3 subunits decreased in expression with age whereas γ2 increased. β2 showed dynamic regulation with early increases plateauing across childhood and adolescence before decreasing in adulthood while β3 levels remained relatively constant. Using published α subunit data we identified two principal components labeled ‘Decreasing’ (α2, α5, β1, γ1 and γ3) and ‘Dynamic’ (α1, α4, β2 and γ2) responsible for 84% of the variation in GABAAR subunit development.
This grouping is generally consistent with the chromosomal localization of subunits, lending credence to regional transcriptional control mechanisms. In addition, understanding developmental changes in GABAAR subunits could foster better pediatric pharmaceutical treatments.</description><identifier>ISSN: 0736-5748</identifier><identifier>EISSN: 1873-474X</identifier><identifier>DOI: 10.1016/j.ijdevneu.2010.05.004</identifier><identifier>PMID: 20609421</identifier><language>eng</language><publisher>United States</publisher><subject>Adolescent ; Adult ; Aging - metabolism ; Child ; Child, Preschool ; Cortical development ; Female ; GABAA gene expression ; GABAA receptor ; GABAA β subunit ; GABAA γ subunit ; Gene Expression Regulation, Developmental - physiology ; Humans ; Infant ; Male ; Middle Aged ; Prefrontal Cortex - physiology ; Receptors, GABA-A - metabolism ; Tissue Distribution ; Young Adult</subject><ispartof>International journal of developmental neuroscience, 2010-10, Vol.28 (6), p.513-519</ispartof><rights>2010 ISDN</rights><rights>Copyright 2010 ISDN. Published by Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1016%2Fj.ijdevneu.2010.05.004$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1016%2Fj.ijdevneu.2010.05.004$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20609421$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fillman, Stu G.</creatorcontrib><creatorcontrib>Duncan, Carlotta E.</creatorcontrib><creatorcontrib>Webster, Maree J.</creatorcontrib><creatorcontrib>Elashoff, Michael</creatorcontrib><creatorcontrib>Weickert, Cynthia Shannon</creatorcontrib><title>Developmental co‐regulation of the β and γ GABAA receptor subunits with distinct α subunits in the human dorsolateral prefrontal cortex</title><title>International journal of developmental neuroscience</title><addtitle>Int J Dev Neurosci</addtitle><description>The GABAA receptor (GABAAR) is a pentameric chloride ion channel that mediates neuronal inhibition and is commonly comprised of 2α, 2β and 1γ subunits. These subunits have distinct characteristics that critically impact receptor function. In this study, we sought to determine if developmental expression of the β and γ subunit mRNAs in the prefrontal cortex would show complementary or opposing patterns of change as compared to the α subunits. Certain GABAAR subunit genes are arranged in tandem on the chromosome, and we hypothesized that genomic proximity would lead to co‐regulation during development.
The mRNA expression of the 3β and 3γ subunits was measured in the human dorsolateral prefrontal cortex of 68 individuals aged neonate to adult, using microarray with qPCR validation. Changes between age groups were identified through ANOVA, linear regression and post hoc Fisher LSD tests while a principal component analysis was used to establish co‐regulation of GABAAR genes.
β1, γ1 and γ3 subunits decreased in expression with age whereas γ2 increased. β2 showed dynamic regulation with early increases plateauing across childhood and adolescence before decreasing in adulthood while β3 levels remained relatively constant. Using published α subunit data we identified two principal components labeled ‘Decreasing’ (α2, α5, β1, γ1 and γ3) and ‘Dynamic’ (α1, α4, β2 and γ2) responsible for 84% of the variation in GABAAR subunit development.
This grouping is generally consistent with the chromosomal localization of subunits, lending credence to regional transcriptional control mechanisms. In addition, understanding developmental changes in GABAAR subunits could foster better pediatric pharmaceutical treatments.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aging - metabolism</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Cortical development</subject><subject>Female</subject><subject>GABAA gene expression</subject><subject>GABAA receptor</subject><subject>GABAA β subunit</subject><subject>GABAA γ subunit</subject><subject>Gene Expression Regulation, Developmental - physiology</subject><subject>Humans</subject><subject>Infant</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Prefrontal Cortex - physiology</subject><subject>Receptors, GABA-A - metabolism</subject><subject>Tissue Distribution</subject><subject>Young Adult</subject><issn>0736-5748</issn><issn>1873-474X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFUcFuEzEUtBCIhsIvVL5x2vB2bWd3j6EJJVFVLhRxsxz7LXG0u15sb0tvfAAHfgX4j3wEX4JDUzg9aWY0ozdDyFkO0xzy2avd1O4M3vQ4TgtIIIgpAH9EJnlVsoyX_ONjMoGSzTJR8uqEPAthBwBCAH9KTgqYQc2LfEK-LfAGWzd02EfVUu1-f_3u8dPYqmhdT11D4xbp_idVvaH7X_Ri_no-px41DtF5GsbN2NsY6K2NW2psiLbXke5__Gds_9diO3aqp8b54JI3-hQ2eGy8O-b6iF-ekyeNagO-ON5Tcv1m-f78bXb57mJ1Pr_MhqKc8azQRgOapsH0A9bIRV1zXtWw0RoZgi4LZsAobao8ZzlWiqlCK1MjKxomNuyUvLz3Hbz7PGKIsrNBY9uqHt0YZGqsFlVRl0l5dlSOmw6NHLztlL-TDwUmwepecGtbvPvH5yAPM8mdfJhJHmaSIGSaSa4XV-vVerH8cLW8PuAgEsr-ANVnkpE</recordid><startdate>201010</startdate><enddate>201010</enddate><creator>Fillman, Stu G.</creator><creator>Duncan, Carlotta E.</creator><creator>Webster, Maree J.</creator><creator>Elashoff, Michael</creator><creator>Weickert, Cynthia Shannon</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>201010</creationdate><title>Developmental co‐regulation of the β and γ GABAA receptor subunits with distinct α subunits in the human dorsolateral prefrontal cortex</title><author>Fillman, Stu G. ; Duncan, Carlotta E. ; Webster, Maree J. ; Elashoff, Michael ; Weickert, Cynthia Shannon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p2764-2cdc0edffe942e9e459944890bcce3e0c723d0dacd81131e8a3a2cad9e32f35b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aging - metabolism</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Cortical development</topic><topic>Female</topic><topic>GABAA gene expression</topic><topic>GABAA receptor</topic><topic>GABAA β subunit</topic><topic>GABAA γ subunit</topic><topic>Gene Expression Regulation, Developmental - physiology</topic><topic>Humans</topic><topic>Infant</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Prefrontal Cortex - physiology</topic><topic>Receptors, GABA-A - metabolism</topic><topic>Tissue Distribution</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fillman, Stu G.</creatorcontrib><creatorcontrib>Duncan, Carlotta E.</creatorcontrib><creatorcontrib>Webster, Maree J.</creatorcontrib><creatorcontrib>Elashoff, Michael</creatorcontrib><creatorcontrib>Weickert, Cynthia Shannon</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of developmental neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fillman, Stu G.</au><au>Duncan, Carlotta E.</au><au>Webster, Maree J.</au><au>Elashoff, Michael</au><au>Weickert, Cynthia Shannon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Developmental co‐regulation of the β and γ GABAA receptor subunits with distinct α subunits in the human dorsolateral prefrontal cortex</atitle><jtitle>International journal of developmental neuroscience</jtitle><addtitle>Int J Dev Neurosci</addtitle><date>2010-10</date><risdate>2010</risdate><volume>28</volume><issue>6</issue><spage>513</spage><epage>519</epage><pages>513-519</pages><issn>0736-5748</issn><eissn>1873-474X</eissn><abstract>The GABAA receptor (GABAAR) is a pentameric chloride ion channel that mediates neuronal inhibition and is commonly comprised of 2α, 2β and 1γ subunits. These subunits have distinct characteristics that critically impact receptor function. In this study, we sought to determine if developmental expression of the β and γ subunit mRNAs in the prefrontal cortex would show complementary or opposing patterns of change as compared to the α subunits. Certain GABAAR subunit genes are arranged in tandem on the chromosome, and we hypothesized that genomic proximity would lead to co‐regulation during development.
The mRNA expression of the 3β and 3γ subunits was measured in the human dorsolateral prefrontal cortex of 68 individuals aged neonate to adult, using microarray with qPCR validation. Changes between age groups were identified through ANOVA, linear regression and post hoc Fisher LSD tests while a principal component analysis was used to establish co‐regulation of GABAAR genes.
β1, γ1 and γ3 subunits decreased in expression with age whereas γ2 increased. β2 showed dynamic regulation with early increases plateauing across childhood and adolescence before decreasing in adulthood while β3 levels remained relatively constant. Using published α subunit data we identified two principal components labeled ‘Decreasing’ (α2, α5, β1, γ1 and γ3) and ‘Dynamic’ (α1, α4, β2 and γ2) responsible for 84% of the variation in GABAAR subunit development.
This grouping is generally consistent with the chromosomal localization of subunits, lending credence to regional transcriptional control mechanisms. In addition, understanding developmental changes in GABAAR subunits could foster better pediatric pharmaceutical treatments.</abstract><cop>United States</cop><pmid>20609421</pmid><doi>10.1016/j.ijdevneu.2010.05.004</doi><tpages>7</tpages></addata></record> |
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subjects | Adolescent Adult Aging - metabolism Child Child, Preschool Cortical development Female GABAA gene expression GABAA receptor GABAA β subunit GABAA γ subunit Gene Expression Regulation, Developmental - physiology Humans Infant Male Middle Aged Prefrontal Cortex - physiology Receptors, GABA-A - metabolism Tissue Distribution Young Adult |
title | Developmental co‐regulation of the β and γ GABAA receptor subunits with distinct α subunits in the human dorsolateral prefrontal cortex |
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