A human-specific microRNA controls the timing of excitatory synaptogenesis

Soutschek, M.; LoBianco, A.; Galkin, S.; Wuest, T.; Colameo, D.; Germade, T.; Gross, F.; von Ziegler, L.; Bohacek, J.; Germain, P.-L.; Winterer, J.; Kleele, T.; Schratt, G.

doi:10.1101/2023.10.04.560889

bioRxiv · 10.1101/2023.10.04.560889

A human-specific microRNA controls the timing of excitatory synaptogenesis

Soutschek, M.·LoBianco, A.·Galkin, S.·Wuest, T.·Colameo, D.·Germade, T.·Gross, F.·von Ziegler, L.·Bohacek, J.·Germain, P.-L.·Winterer, J.·Kleele, T.·Schratt, G.

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Abstract

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. One-Sentence SummaryA human-specific microRNA slows down the formation and maturation of neuronal synapses by reducing mitochondrial metabolism.

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Soutschek, M., LoBianco, A., Galkin, S., Wuest, T., Colameo, D., Germade, T., Gross, F., von Ziegler, L., Bohacek, J., Germain, P.-L., Winterer, J., Kleele, T., Schratt, G.. 2023-10-05. A human-specific microRNA controls the timing of excitatory synaptogenesis. https://doi.org/10.1101/2023.10.04.560889

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