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Transl Psychiatry. 2015 Feb 17;5:e511. doi: 10.1038/tp.2015.11.

MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression.

Author information

1
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.
2
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.
3
McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
4
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.
5
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.

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.

PMID:
25689572
PMCID:
PMC4445749
DOI:
10.1038/tp.2015.11
[Indexed for MEDLINE]
Free PMC Article

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