Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression
Identifieur interne : 000561 ( France/Analysis ); précédent : 000560; suivant : 000562Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression
Auteurs : J.-P. Guilloux [États-Unis, France] ; G. Douillard-Guilloux [États-Unis] ; R. Kota [États-Unis] ; X. Wang [États-Unis] ; A. M. Gardier [France] ; K. Martinowich [États-Unis] ; G. C. Tseng [États-Unis] ; D. A. Lewis [États-Unis] ; E. Sibille [États-Unis]Source :
- Molecular psychiatry [ 1359-4184 ] ; 2012.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
Abstract
Women are twice as likely as men to develop major depressive disorder (MDD) and are more prone to recurring episodes. Hence, we tested the hypothesis that the illness may associate with robust molecular changes in female subjects, and investigated large-scale gene expression in the post-mortem brain of MDD subjects paired with matched controls (n= 21 pairs). We focused on the lateral/basolateral/basomedian complex of the amygdala as a neural hub of mood regulation affected in MDD. Among the most robust findings were downregulated transcripts for genes coding for γ-aminobutyric acid (GABA) interneuronrelated peptides, including somatostatin (SST), tachykinin, neuropeptide Y (NPY) and cortistatin, in a pattern reminiscent to that previously reported in mice with low brain-derived neurotrophic factor (BDNF). Changes were confirmed by quantitative PCR and not explained by demographic, technical or known clinical parameters. BDNF itself was significantly downregulated at the RNA and protein levels in MDD subjects. Investigating putative mechanisms, we show that this core MDD-related gene profile (including SST, NPY, TAC1, RGS4 and CORT) is recapitulated by complementary patterns in mice with constitutive (BDNF-heterozygous) or activity-dependent (exon IV knockout) decreases in BDNF function, with a common effect on SST and NPY. Together, these results provide both direct (low RNA/protein) and indirect (low BDNF-dependent gene pattern) evidence for reduced BDNF function in the amygdala of female subjects with MDD. Supporting studies in mutant mice models suggest a complex mechanism of low constitutive and activity-dependent BDNF function in MDD, particularly affecting SST/NPY-related GABA neurons, thus linking the neurotrophic and GABA hypotheses of depression.
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Guilloux</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Psychiatry, University of Pittsburgh</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>EA 3544, Univ Paris-Sud, Fac. Pharmacie</s1><s2>Châtenay-Malabry</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Châtenay-Malabry</wicri:noRegion><wicri:noRegion>Fac. Pharmacie</wicri:noRegion><wicri:noRegion>Châtenay-Malabry</wicri:noRegion></affiliation></author><author><name sortKey="Douillard Guilloux, G" sort="Douillard Guilloux, G" uniqKey="Douillard Guilloux G" first="G." last="Douillard-Guilloux">G. Douillard-Guilloux</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Psychiatry, University of Pittsburgh</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Kota, R" sort="Kota, R" uniqKey="Kota R" first="R." last="Kota">R. Kota</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Psychiatry, University of Pittsburgh</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Wang, X" sort="Wang, X" uniqKey="Wang X" first="X." last="Wang">X. Wang</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Biostatistics, University of Pittsburgh</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Gardier, A M" sort="Gardier, A M" uniqKey="Gardier A" first="A. M." last="Gardier">A. M. Gardier</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>EA 3544, Univ Paris-Sud, Fac. Pharmacie</s1><s2>Châtenay-Malabry</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Châtenay-Malabry</wicri:noRegion><wicri:noRegion>Fac. Pharmacie</wicri:noRegion><wicri:noRegion>Châtenay-Malabry</wicri:noRegion></affiliation></author><author><name sortKey="Martinowich, K" sort="Martinowich, K" uniqKey="Martinowich K" first="K." last="Martinowich">K. Martinowich</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Genes, Cognition and Psychosis Program (GCAP), National Institute of Mental Health (NIMH</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Bethesda, MD</wicri:noRegion></affiliation></author><author><name sortKey="Tseng, G C" sort="Tseng, G C" uniqKey="Tseng G" first="G. C." last="Tseng">G. C. Tseng</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Biostatistics, University of Pittsburgh</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Lewis, D A" sort="Lewis, D A" uniqKey="Lewis D" first="D. A." last="Lewis">D. A. Lewis</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Psychiatry, University of Pittsburgh</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="05"><s1>Center for Neuroscience, University of Pittsburgh</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author><author><name sortKey="Sibille, E" sort="Sibille, E" uniqKey="Sibille E" first="E." last="Sibille">E. Sibille</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Psychiatry, University of Pittsburgh</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="05"><s1>Center for Neuroscience, University of Pittsburgh</s1><s2>Pittsburgh, PA</s2><s3>USA</s3><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><orgName type="university">Université de Pittsburgh</orgName></affiliation></author></analytic><series><title level="j" type="main">Molecular psychiatry</title><title level="j" type="abbreviated">Mol. psychiatry</title><idno type="ISSN">1359-4184</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Molecular psychiatry</title><title level="j" type="abbreviated">Mol. psychiatry</title><idno type="ISSN">1359-4184</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amygdala</term><term>Amygdaloid nucleus</term><term>Brain derived neurotrophic factor</term><term>Depression</term><term>Female</term><term>GABA</term><term>Human</term><term>Somatostatin</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Facteur BDNF</term><term>GABA</term><term>Noyau amygdalien</term><term>Amygdale</term><term>Etat dépressif</term><term>Somatostatine</term><term>Femelle</term><term>Homme</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Women are twice as likely as men to develop major depressive disorder (MDD) and are more prone to recurring episodes. Hence, we tested the hypothesis that the illness may associate with robust molecular changes in female subjects, and investigated large-scale gene expression in the post-mortem brain of MDD subjects paired with matched controls (n= 21 pairs). We focused on the lateral/basolateral/basomedian complex of the amygdala as a neural hub of mood regulation affected in MDD. Among the most robust findings were downregulated transcripts for genes coding for γ-aminobutyric acid (GABA) interneuronrelated peptides, including somatostatin (SST), tachykinin, neuropeptide Y (NPY) and cortistatin, in a pattern reminiscent to that previously reported in mice with low brain-derived neurotrophic factor (BDNF). Changes were confirmed by quantitative PCR and not explained by demographic, technical or known clinical parameters. BDNF itself was significantly downregulated at the RNA and protein levels in MDD subjects. Investigating putative mechanisms, we show that this core MDD-related gene profile (including SST, NPY, TAC1, RGS4 and CORT) is recapitulated by complementary patterns in mice with constitutive (BDNF-heterozygous) or activity-dependent (exon IV knockout) decreases in BDNF function, with a common effect on SST and NPY. Together, these results provide both direct (low RNA/protein) and indirect (low BDNF-dependent gene pattern) evidence for reduced BDNF function in the amygdala of female subjects with MDD. Supporting studies in mutant mice models suggest a complex mechanism of low constitutive and activity-dependent BDNF function in MDD, particularly affecting SST/NPY-related GABA neurons, thus linking the neurotrophic and GABA hypotheses of depression.</div></front></TEI><affiliations><list><country><li>France</li><li>États-Unis</li></country><region><li>Pennsylvanie</li></region><settlement><li>Pittsburgh</li></settlement><orgName><li>Université de Pittsburgh</li></orgName></list><tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Guilloux, J P" sort="Guilloux, J P" uniqKey="Guilloux J" first="J.-P." last="Guilloux">J.-P. Guilloux</name></region><name sortKey="Douillard Guilloux, G" sort="Douillard Guilloux, G" uniqKey="Douillard Guilloux G" first="G." last="Douillard-Guilloux">G. Douillard-Guilloux</name><name sortKey="Kota, R" sort="Kota, R" uniqKey="Kota R" first="R." last="Kota">R. Kota</name><name sortKey="Lewis, D A" sort="Lewis, D A" uniqKey="Lewis D" first="D. A." last="Lewis">D. A. Lewis</name><name sortKey="Lewis, D A" sort="Lewis, D A" uniqKey="Lewis D" first="D. A." last="Lewis">D. A. Lewis</name><name sortKey="Martinowich, K" sort="Martinowich, K" uniqKey="Martinowich K" first="K." last="Martinowich">K. Martinowich</name><name sortKey="Sibille, E" sort="Sibille, E" uniqKey="Sibille E" first="E." last="Sibille">E. Sibille</name><name sortKey="Sibille, E" sort="Sibille, E" uniqKey="Sibille E" first="E." last="Sibille">E. Sibille</name><name sortKey="Tseng, G C" sort="Tseng, G C" uniqKey="Tseng G" first="G. C." last="Tseng">G. C. Tseng</name><name sortKey="Wang, X" sort="Wang, X" uniqKey="Wang X" first="X." last="Wang">X. Wang</name></country><country name="France"><noRegion><name sortKey="Guilloux, J P" sort="Guilloux, J P" uniqKey="Guilloux J" first="J.-P." last="Guilloux">J.-P. Guilloux</name></noRegion><name sortKey="Gardier, A M" sort="Gardier, A M" uniqKey="Gardier A" first="A. M." last="Gardier">A. M. Gardier</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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