MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression.
Title | MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Maheu M, Lopez JP, Crapper L, Davoli MA, Turecki G, Mechawar N |
Journal | Transl Psychiatry |
Volume | 5 |
Pagination | e511 |
Date Published | 2015 |
ISSN | 2158-3188 |
Keywords | Adult, Amygdala, Case-Control Studies, Depressive Disorder, Major, Down-Regulation, Female, Glial Cell Line-Derived Neurotrophic Factor, Glial Cell Line-Derived Neurotrophic Factor Receptors, Humans, Male, MAP Kinase Signaling System, MicroRNAs, Microtubule-Associated Proteins, Middle Aged, Neural Cell Adhesion Molecules, Neuropeptides, Proto-Oncogene Proteins c-ret, RNA, Messenger, Signal Transduction, Young Adult |
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. |
DOI | 10.1038/tp.2015.11 |
Alternate Journal | Transl Psychiatry |
PubMed ID | 25689572 |
PubMed Central ID | PMC4445749 |
Grant List | MOP-111022 / / Canadian Institutes of Health Research / Canada |