Despite the emerging knowledge on the importance of miRNAs in brain function and disease, very little is known about the role of miRNAs in BD. Here we show that miR-34a is upregulated in post-mortem BD brain and in two different patient-derived cellular models of BD, and is predicted to target multiple genes implicated in the etiology of BD through recent GWAS studies16, 30. In addition, we validate ANK3, CACNB3, and DDN as novel targets of miR-34a and implicate a molecular network of miR-34a targets. Lastly, we demonstrate using human iPSC-derived neuronal cultures that miR-34a expression is negatively correlated to that of ANK3 and CACNB3 and impairs neuronal differentiation and morphology. In this context, our finding that expression of an anti-miR-34a construct that traps endogenous miR-34a is sufficient to enhance dendritogenesis is particularly intriguing as it provides evidence that levels of one or more miR-34a target genes are rate-limiting for dendritic elaboration in human neurons.
