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

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 GFR alpha 1a protein levels in basolateral amygdala (BLA) samples from depressed subjects. Downregulation of GFR alpha 1a 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 GFR alpha 1a. Transfection of human neural progenitor cells (NPCs) with a miR-511 mimic was sufficient to repress GFRA1-L/GFR alpha 1a without altering GFR alpha 1b, and resulted in pathway-specific changes in immediate early gene activity. Unexpectedly, GFR alpha 1a 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 GFR alpha 1/neural cell adhesion molecule binding, and substituting the soluble GFR alpha 1a/GFR alpha 1b content of miR-511transfected NPCs with that of controls rescued signalling. In light of previous reports suggesting that GFR alpha 1b can inhibit GFR alpha 1a-induced neuroplasticity, we also assessed the association between GFR alpha 1 and doublecortin (DCX; a hyperplastic marker) in human BLA. Although controls displayed coordinated expression of GFR alpha 1a and b isoforms and these correlated positively with DCX, the only significant association observed among depressed subjects was a strongly negative correlation between GFR alpha 1b and DCX. Taken together, these results suggest that microRNA-mediated reductions of GFR alpha 1a 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.