Decreased expression of synapse-related genes and loss of synapses in major depressive disorder
Ronald Duman and colleagues report that synapse number is reduced in subjects with major depressive disorder. This is associated with decreased expression of synapse-related genes and increased expression of the transcriptional repressor, GATA1. Expression of GATA1 in prefrontal cortex neurons decre...
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| Veröffentlicht in: | Nature medicine 2012-09, Vol.18 (9), p.1413-1417 |
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| creator | Kang, Hyo Jung Voleti, Bhavya Hajszan, Tibor Rajkowska, Grazyna Stockmeier, Craig A Licznerski, Pawel Lepack, Ashley Majik, Mahesh S Jeong, Lak Shin Banasr, Mounira Son, Hyeon Duman, Ronald S |
| description | Ronald Duman and colleagues report that synapse number is reduced in subjects with major depressive disorder. This is associated with decreased expression of synapse-related genes and increased expression of the transcriptional repressor, GATA1. Expression of GATA1 in prefrontal cortex neurons decreases the expression of synapse-related genes, reduces dendrite branching and produces depressive behavior in a rat model of depression.
Previous imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD)
1
,
2
. These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function–related genes (
CALM2
,
SYN1
,
RAB3A
,
RAB4B
and
TUBB4
) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression. |
| doi_str_mv | 10.1038/nm.2886 |
| format | Article |
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Previous imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD)
1
,
2
. These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function–related genes (
CALM2
,
SYN1
,
RAB3A
,
RAB4B
and
TUBB4
) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/nm.2886</identifier><identifier>PMID: 22885997</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/378/340 ; 692/699/476/1414 ; Analysis of Variance ; Animals ; Biomedical and Life Sciences ; Biomedicine ; Calmodulin - metabolism ; Cancer Research ; Cell Line ; Dendrites ; Depressive Disorder, Major - metabolism ; Depressive Disorder, Major - pathology ; GATA1 Transcription Factor - metabolism ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation - physiology ; Humans ; Infectious Diseases ; letter ; Mental depression ; Metabolic Diseases ; Microarray Analysis ; Microscopy, Electron ; Molecular Medicine ; Neurons ; Neurosciences ; Polymerase chain reaction ; Prefrontal Cortex - pathology ; rab3A GTP-Binding Protein - metabolism ; rab4 GTP-Binding Proteins - metabolism ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Synapses - metabolism ; Synapses - pathology ; Synapsins - metabolism ; Tubulin - metabolism</subject><ispartof>Nature medicine, 2012-09, Vol.18 (9), p.1413-1417</ispartof><rights>Springer Nature America, Inc. 2012</rights><rights>Copyright Nature Publishing Group Sep 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-21904a2ad8868ac08989c3bba4f3713e54b59d23180887dd7b4906af69f209813</citedby><cites>FETCH-LOGICAL-c529t-21904a2ad8868ac08989c3bba4f3713e54b59d23180887dd7b4906af69f209813</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nm.2886$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nm.2886$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22885997$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kang, Hyo Jung</creatorcontrib><creatorcontrib>Voleti, Bhavya</creatorcontrib><creatorcontrib>Hajszan, Tibor</creatorcontrib><creatorcontrib>Rajkowska, Grazyna</creatorcontrib><creatorcontrib>Stockmeier, Craig A</creatorcontrib><creatorcontrib>Licznerski, Pawel</creatorcontrib><creatorcontrib>Lepack, Ashley</creatorcontrib><creatorcontrib>Majik, Mahesh S</creatorcontrib><creatorcontrib>Jeong, Lak Shin</creatorcontrib><creatorcontrib>Banasr, Mounira</creatorcontrib><creatorcontrib>Son, Hyeon</creatorcontrib><creatorcontrib>Duman, Ronald S</creatorcontrib><title>Decreased expression of synapse-related genes and loss of synapses in major depressive disorder</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>Ronald Duman and colleagues report that synapse number is reduced in subjects with major depressive disorder. This is associated with decreased expression of synapse-related genes and increased expression of the transcriptional repressor, GATA1. Expression of GATA1 in prefrontal cortex neurons decreases the expression of synapse-related genes, reduces dendrite branching and produces depressive behavior in a rat model of depression.
Previous imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD)
1
,
2
. These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function–related genes (
CALM2
,
SYN1
,
RAB3A
,
RAB4B
and
TUBB4
) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression.</description><subject>631/378/340</subject><subject>692/699/476/1414</subject><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Calmodulin - metabolism</subject><subject>Cancer Research</subject><subject>Cell Line</subject><subject>Dendrites</subject><subject>Depressive Disorder, Major - metabolism</subject><subject>Depressive Disorder, Major - pathology</subject><subject>GATA1 Transcription Factor - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation - physiology</subject><subject>Humans</subject><subject>Infectious Diseases</subject><subject>letter</subject><subject>Mental depression</subject><subject>Metabolic Diseases</subject><subject>Microarray Analysis</subject><subject>Microscopy, Electron</subject><subject>Molecular Medicine</subject><subject>Neurons</subject><subject>Neurosciences</subject><subject>Polymerase chain reaction</subject><subject>Prefrontal Cortex - pathology</subject><subject>rab3A GTP-Binding Protein - metabolism</subject><subject>rab4 GTP-Binding Proteins - metabolism</subject><subject>Rats</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Synapses - metabolism</subject><subject>Synapses - pathology</subject><subject>Synapsins - metabolism</subject><subject>Tubulin - metabolism</subject><issn>1078-8956</issn><issn>1546-170X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkU9r3DAQxUVoadK05BsUQQ_pxclIsmzpEgjpXwj0kkJvQrbGWy-2tNHshuTbV8um6TaXnjTwfjzNm8fYiYAzAcqcx_lMGtMcsCOh66YSLfx8UWZoTWWsbg7Za6IlACjQ9hU7lAXW1rZHzH3EPqMnDBzvVxmJxhR5Gjg9RL8irDJOfl3UBUYk7mPgUyLaI4iPkc9-mTIPuHO4Qx5GSjlgfsNeDn4ifPv4HrMfnz_dXH2trr9_-XZ1eV31Wtp1JYWF2ksfSgjjezDW2F51na8H1QqFuu60DVIJA8a0IbRdbaHxQ2MHCdYIdcwudr6rTTdj6DGus5_cKo-zzw8u-dH9q8Txl1ukO6dqK4TQxeDDo0FOtxuktZtH6nGafMS0ISdqZaUyUsH_UVGXFgDEdq33z9Bl2uRYLuGENCVC02hTqNMd1edy24zD094C3LZfF2e37beQ7_ZjPnF_Cv27GxUpLjDvffjM6zdbfq4d</recordid><startdate>20120901</startdate><enddate>20120901</enddate><creator>Kang, Hyo Jung</creator><creator>Voleti, Bhavya</creator><creator>Hajszan, Tibor</creator><creator>Rajkowska, Grazyna</creator><creator>Stockmeier, Craig A</creator><creator>Licznerski, Pawel</creator><creator>Lepack, Ashley</creator><creator>Majik, Mahesh S</creator><creator>Jeong, Lak Shin</creator><creator>Banasr, Mounira</creator><creator>Son, Hyeon</creator><creator>Duman, Ronald S</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20120901</creationdate><title>Decreased expression of synapse-related genes and loss of synapses in major depressive disorder</title><author>Kang, Hyo Jung ; Voleti, Bhavya ; Hajszan, Tibor ; Rajkowska, Grazyna ; Stockmeier, Craig A ; Licznerski, Pawel ; Lepack, Ashley ; Majik, Mahesh S ; Jeong, Lak Shin ; Banasr, Mounira ; Son, Hyeon ; Duman, Ronald S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-21904a2ad8868ac08989c3bba4f3713e54b59d23180887dd7b4906af69f209813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>631/378/340</topic><topic>692/699/476/1414</topic><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Calmodulin - metabolism</topic><topic>Cancer Research</topic><topic>Cell Line</topic><topic>Dendrites</topic><topic>Depressive Disorder, Major - metabolism</topic><topic>Depressive Disorder, Major - pathology</topic><topic>GATA1 Transcription Factor - metabolism</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation - physiology</topic><topic>Humans</topic><topic>Infectious Diseases</topic><topic>letter</topic><topic>Mental depression</topic><topic>Metabolic Diseases</topic><topic>Microarray Analysis</topic><topic>Microscopy, Electron</topic><topic>Molecular Medicine</topic><topic>Neurons</topic><topic>Neurosciences</topic><topic>Polymerase chain reaction</topic><topic>Prefrontal Cortex - pathology</topic><topic>rab3A GTP-Binding Protein - metabolism</topic><topic>rab4 GTP-Binding Proteins - metabolism</topic><topic>Rats</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Synapses - metabolism</topic><topic>Synapses - pathology</topic><topic>Synapsins - metabolism</topic><topic>Tubulin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kang, Hyo Jung</creatorcontrib><creatorcontrib>Voleti, Bhavya</creatorcontrib><creatorcontrib>Hajszan, Tibor</creatorcontrib><creatorcontrib>Rajkowska, Grazyna</creatorcontrib><creatorcontrib>Stockmeier, Craig A</creatorcontrib><creatorcontrib>Licznerski, Pawel</creatorcontrib><creatorcontrib>Lepack, Ashley</creatorcontrib><creatorcontrib>Majik, Mahesh S</creatorcontrib><creatorcontrib>Jeong, Lak Shin</creatorcontrib><creatorcontrib>Banasr, Mounira</creatorcontrib><creatorcontrib>Son, Hyeon</creatorcontrib><creatorcontrib>Duman, Ronald S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kang, Hyo Jung</au><au>Voleti, Bhavya</au><au>Hajszan, Tibor</au><au>Rajkowska, Grazyna</au><au>Stockmeier, Craig A</au><au>Licznerski, Pawel</au><au>Lepack, Ashley</au><au>Majik, Mahesh S</au><au>Jeong, Lak Shin</au><au>Banasr, Mounira</au><au>Son, Hyeon</au><au>Duman, Ronald S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Decreased expression of synapse-related genes and loss of synapses in major depressive disorder</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2012-09-01</date><risdate>2012</risdate><volume>18</volume><issue>9</issue><spage>1413</spage><epage>1417</epage><pages>1413-1417</pages><issn>1078-8956</issn><eissn>1546-170X</eissn><abstract>Ronald Duman and colleagues report that synapse number is reduced in subjects with major depressive disorder. This is associated with decreased expression of synapse-related genes and increased expression of the transcriptional repressor, GATA1. Expression of GATA1 in prefrontal cortex neurons decreases the expression of synapse-related genes, reduces dendrite branching and produces depressive behavior in a rat model of depression.
Previous imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD)
1
,
2
. These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function–related genes (
CALM2
,
SYN1
,
RAB3A
,
RAB4B
and
TUBB4
) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>22885997</pmid><doi>10.1038/nm.2886</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | MEDLINE; Nature; SpringerLink Journals - AutoHoldings |
| subjects | 631/378/340 692/699/476/1414 Analysis of Variance Animals Biomedical and Life Sciences Biomedicine Calmodulin - metabolism Cancer Research Cell Line Dendrites Depressive Disorder, Major - metabolism Depressive Disorder, Major - pathology GATA1 Transcription Factor - metabolism Gene expression Gene Expression Profiling Gene Expression Regulation - physiology Humans Infectious Diseases letter Mental depression Metabolic Diseases Microarray Analysis Microscopy, Electron Molecular Medicine Neurons Neurosciences Polymerase chain reaction Prefrontal Cortex - pathology rab3A GTP-Binding Protein - metabolism rab4 GTP-Binding Proteins - metabolism Rats Reverse Transcriptase Polymerase Chain Reaction Synapses - metabolism Synapses - pathology Synapsins - metabolism Tubulin - metabolism |
| title | Decreased expression of synapse-related genes and loss of synapses in major depressive disorder |
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