Circulating extracellular microRNAs in the blood promote sociability in mice

Dohi, E.; Matoba, K.; Garcia, P. A.; Francis-Oliveira, J.; Anguiano, F.; Kochi, T.; Badrani, J. H.; See, J.; Ito, N.; Mitani, R.; Rose, I. V.; Choi, E. Y.; Imai, T.; Crossman, D. K.; Pletnikov, M. V.; Witwer, K. W.; Niwa, M.; Kano, S.

doi:10.1101/2024.08.12.605506

bioRxiv · 10.1101/2024.08.12.605506

Circulating extracellular microRNAs in the blood promote sociability in mice

Dohi, E.·Matoba, K.·Garcia, P. A.·Francis-Oliveira, J.·Anguiano, F.·Kochi, T.·Badrani, J. H.·See, J.·Ito, N.·Mitani, R.·Rose, I. V.·Choi, E. Y.·Imai, T.·Crossman, D. K.·Pletnikov, M. V.·Witwer, K. W.·Niwa, M.·Kano, S.

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Abstract

Extracellular vesicles (EVs) are cell-derived small membrane vesicles and circulate throughout the body, but the impact of circulating EVs on brain function and behavior remains elusive. Here, we report that wild-type (WT) mouse blood, particularly EVs, increases sociability in socially impaired immunodeficient Rag1-/- mice, mimicking the effects of WT T cell transfer. These EVs localized to neurons and regulated PKC{varepsilon} expression, GABAA receptor synaptic localization, and inhibitory postsynaptic signaling in prefrontal cortex (PFC) pyramidal neurons. Injection of Rag1-/- EVs supplemented with miR-23a-3p and miR-103-3p enhanced synaptic function and sociability in Rag1-/- mice. T cells secreted miR-23a-3p via EVs, and Mir23a-/- T cells failed to increase sociability. Similar beneficial effects of WT blood EVs were observed in additional mouse models with sociability deficits, Cntnap2-/- and Shank3-/- mice. These findings uncover a previously unrecognized role of EV miRNAs in mediating immune modulation of synaptic function and social behavior, revealing a novel molecular pathway for immune-neuron communication.

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Dohi, E., Matoba, K., Garcia, P. A., Francis-Oliveira, J., Anguiano, F., Kochi, T., Badrani, J. H., See, J., Ito, N., Mitani, R., Rose, I. V., Choi, E. Y., Imai, T., Crossman, D. K., Pletnikov, M. V., Witwer, K. W., Niwa, M., Kano, S.. 2024-08-16. Circulating extracellular microRNAs in the blood promote sociability in mice. https://doi.org/10.1101/2024.08.12.605506

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