In the context of BD pharmacology, miR-34a, which belongs to the broadly evolutionarily conserved miR-34 microRNA family, has been shown to be reduced by lithium and valproic acid, two chemically distinct medications commonly used in the long-term treatment of BD24, 25. Moreover, miR-34a can influence mouse neuronal development26 and its validated targets have been shown to be involved in neuronal differentiation, synaptic plasticity and long-term memory in mammals27–29. On the basis of these findings, we hypothesized that miR-34a could serve as an important link between emerging genetic risk factors for BD. Here, we show that miR-34a levels are increased in the cerebellum of BD subjects as well as in human neuronal cultures from reprogrammed patient cells. In addition, we provide evidence that miR-34a targets BD-related genes ANK3 and CACNB3, and regulates their expression during neuronal differentiation. Elevation of miR-34a expression in human iPSC-derived neuronal progenitors affected ANK3 and CACNB3 mRNA and protein expression and resulted in defects in neuronal differentiation as measured morphologically and biochemically through analysis of pre- and post-synaptic markers. Conversely, suppression of miR-34a expression enhanced dendritogenesis. Expanded
