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.

Exercise-Mediated Increase in Nigral Tyrosine Hydroxylase Is Accompanied by Increased Nigral GFR-α1 and EAAC1 Expression in Aging Rats

“…49 Furthermore, a specific decrease in an isoform of GFR- α 1 has been shown in the basolateral amygdala of depressed patients. 50 Exercise has been shown to be effective in reducing cognitive impairment 51 and depressive-like behavior. 52 The involvement of increased GFR- α 1 expression following exercise to reduce these adverse behavioral outcomes is possible, though yet unknown.…”

GDNF and alcohol use disorder

“…Polymorphism within the Gdnf gene has been reported to be associated with increased risk of depression (Ma et al 2013) and anxiety disorders (Kotyuk et al 2013). Moreover, in a post-mortem study, GFRα1 levels were reduced in the basolateral amygdala of patients that suffered from depression and correlated with the increased expression of microRNAs that target the receptor (Maheu et al 2015). Interestingly, serum GDNF levels have been correlated with mood assessments.…”

<p>Identification of key genes, pathways and miRNA/mRNA regulatory networks of CUMS-induced depression in nucleus accumbens by integrated bioinformatics analysis</p>

“…21 Gene expression disturbance in the brain is most probably linked with environmental factors which lead to depression. 22,23 This assumption has been established by analyzing miRNA in depressive patients 24,25 and in mice with depression-like behaviors. 26 A reaction chain from stress to miRNA dysregulation, alternations in mRNA/ protein expression, and neuron atrophy and function deficit are proposed to be associated with MDD.…”