Chronic treatment with either lithium or valproic acid, which are the most effective mood-stabilizers, reduces miR-34a expression in vivo and in neuronal cultures25. On a similar note, chronic lithium and valproic acid co-treatment has been reported to downregulate miR-34a levels in rodent cerebellar granule cell cultures24. On the other hand, lithium treatment appears to have opposite effects in miR-34a expression in human peripheral blood-derived, lymphoblastoid cell lines54. More importantly, miR-34a has been shown in non-neuronal cells to be a strong inhibitor of WNT signalling and β-catenin-mediated transcription in response to p53 activation in non-neuronal cells69, 70. Recent findings have demonstrated that ANK3 regulates both cadherin and WNT signaling pathways by altering the availability of β-catenin with ANK3 loss-of-function impacting neurogenesis71, supporting the importance of WNT signaling in the etiology of neurodevelopmental disorders. Given the effects of lithium on WNT signalling, it is, therefore, intriguing to speculate that high miR-34a expression could be important for the pathophysiology of BD through this pathway, and that the delayed therapeutic effects of mood stabilizers could be partly attributed in their capacity to reduce miR-34a levels following chronic treatment.
