MiR‐223 regulates immature neurons excitability and dendritic development

Differentiation of neural stem/progenitor cells (NS/PCs) into neurons and incorporation into neuronal circuitry is crucial for success of stem cell therapy in the CNS. MicroRNAs are endogenous small non‐coding regulatory RNA molecules that are involved in regulation of stem cell function. To identify microRNAs involved in NS/PCs differentiation, we performed miRNA profiling in normal human neural progenitors (NHNPs) before and after differentiation in vitro. We observed a widespread upregulation of miRNAs following differentiation of NHNPs. MicroRNAs associated with neuronal differentiation such as miR‐124, 132, 134, and miR‐200 were upregulated. The fact that many miRNAs did not change and fewer miRNAs were downregulated suggests that the effects observed are specific to the miRNAs assayed rather than a global effect. We identified multiple miRNAs that are not known to be associated with neural differentiation including miR‐223. To investigate its effect on NS/PCs differentiation, we used recombinant viral vectors to overexpress or inhibit miR‐223. Inhibition of miR‐223 in the adult mouse dentate gyrus NS/PCs led to a significant increase in immature neurons dendritic tree total length, branch number per neuron and complexity as determined by Sholl analysis. Moreover, MiR‐223 overexpression inhibited and its knockdown enhanced NMDA induced calcium influx in human neurons differentiated from NHNPs. Taken together, our results suggest that miR‐223 regulates the NS/PCs derived neurons integration into neuronal circuitry. This work was supported by NIH 2P50DA000266. MMH was supported by MSCRF PDF # 104278.