A human-specific microRNA controls the timing of excitatory synaptogenesis (time course smallRNA)

Neural circuit development in the human cortex is considerably prolonged in comparison to non-human primates, a trait that contributes to the remarkable cognitive capacity of modern humans. Here, we explore the regulatory role of non-coding RNAs, which dramatically expanded during brain evolution, in synapse development of human-induced pluripotent stem-cell derived neurons. We found that inhibition of a human-specific microRNA, miR-1229-3p, alters the trajectory of human neuronal maturation and enhances excitatory synaptic transmission. Transcriptome analysis following miR-1229 knockdown revealed a downregulation of mitochondrial DNA (mtDNA) encoded genes. We further show that miR-1229 regulates mitochondrial morphology, mtDNA abundance and matrix calcium concentration, and that stimulation of mitochondrial metabolism rescues decreased calcium buffering in miR-1229-3p depleted neurons. Accordingly, miR-1229 directly targets an entire network of genes involved in mitochondrial function and ER-associated protein homeostasis. Our findings reveal an important function of human-specific miR-1229-3p in developmental timing of human synaptogenesis and generally implicate non-coding RNAs in the control of human connectivity and cognition. Overall design: To investigat gene expression during human neuronal differentiation, we differentiated hiPSC into human neurons following an optimized protocol ("igNeurons"). RNA from these differentiations was extracted at seven time points (Day 0, Day 9, Day 15, Day 21, Day 27, Day 33 & Day 40) and sent for "Ribosomal Depletion"- as well as "SmallRNA"- sequencing.