title: MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression.
abstract: Although multiple studies have reported that peripheral glial cell line-derived neurotrophic factor (GDNF) is reduced in depression, cerebral GDNF signalling has yet to be examined in this condition. Here, we report an isoform-specific decrease in GDNF family receptor alpha 1 (GFRA1) mRNA expression, resulting in lowered GFRα1a protein levels in basolateral amygdala (BLA) samples from depressed subjects. Downregulation of GFRα1a was associated with increased expression of microRNAs, including miR-511, predicted to bind to long 3' untranslated region (3'-UTR)-containing transcripts (GFRA1-L) coding for GFRα1a. Transfection of human neural progenitor cells (NPCs) with a miR-511 mimic was sufficient to repress GFRA1-L/GFRα1a without altering GFRα1b, and resulted in pathway-specific changes in immediate early gene activity. Unexpectedly, GFRα1a knockdown did not reduce NPC responses to GDNF. Rather, it greatly enhanced mitogen-activated protein kinase signalling. This effect appeared to be mediated by GDNF/soluble GFRα1/neural cell adhesion molecule binding, and substituting the soluble GFRα1a/GFRα1b content of miR-511-transfected NPCs with that of controls rescued signalling. In light of previous reports suggesting that GFRα1b can inhibit GFRα1a-induced neuroplasticity, we also assessed the association between GFRα1 and doublecortin (DCX; a hyperplastic marker) in human BLA. Although controls displayed coordinated expression of GFRα1a and b isoforms and these correlated positively with DCX, the only significant association observed among depressed subjects was a strongly negative correlation between GFRα1b and DCX. Taken together, these results suggest that microRNA-mediated reductions of GFRα1a in depression change the quality, rather than the quantity, of GDNF signalling. They also suggest that central GDNF signalling may represent a novel target for antidepressant treatment.
authors.affiliation: 1] McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada [2] Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Maheu
authors.affiliation: 1] McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada [2] Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: J P
authors.initials: JP
authors.lastname: Lopez
authors.affiliation: 1] McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada [2] Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Crapper
authors.affiliation: McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: Davoli
authors.affiliation: 1] McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada [2] Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada [3] Department of Human Genetics, McGill University, Montreal, QC, Canada [4] Department of Psychiatry, McGill University, Montreal, QC, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Turecki
authors.affiliation: 1] McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada [2] Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada [3] Department of Psychiatry, McGill University, Montreal, QC, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Mechawar
mesh_terms: D000328:Adult; D000679:Amygdala / Q000378:metabolism*; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D015536:Down-Regulation; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D019006:Neural Cell Adhesion Molecules; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
chemical_list: C000714328:DCX protein, human; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C570046:MIRN340 microRNA, human; C578471:MIRN511 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D019006:Neural Cell Adhesion Molecules; D009479:Neuropeptides; D012333:RNA, Messenger; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human