LAUSR

Significance Exosomes have been implicated in intercellular communication in cancer and neurodegenerative disorders. We explored their function in brain development. Proteomic analysis demonstrated that exosomes from isogenic control cultures contain neurodevelopmental signaling proteins, which are lacking in exosomes from MECP2 loss-of-function (MECP2LOF) cultures. Treating MECP2LOF neural cultures with control exosomes rescues neurodevelopmental deficits, increasing neurogenesis, synaptogenesis, and network activity. Exosomes function similarly in vivo: injecting purified exosomes into the lateral ventricles of P4 mouse brains increased hippocampal neurogenesis. These findings significantly advance the field by demonstrating that neural exosomes contain diverse protein cargo predicted to affect multiple outcome measures of neural development and that exosomes signal between cells in developing neural circuits to promote neural circuit development and function. Exosomes are thought to be released by all cells in the body and to be involved in intercellular communication. We tested whether neural exosomes can regulate the development of neural circuits. We show that exosome treatment increases proliferation in developing neural cultures and in vivo in dentate gyrus of P4 mouse brain. We compared the protein cargo and signaling bioactivity of exosomes released by hiPSC-derived neural cultures lacking MECP2, a model of the neurodevelopmental disorder Rett syndrome, with exosomes released by isogenic rescue control neural cultures. Quantitative proteomic analysis indicates that control exosomes contain multiple functional signaling networks known to be important for neuronal circuit development. Treating MECP2-knockdown human primary neural cultures with control exosomes rescues deficits in neuronal proliferation, differentiation, synaptogenesis, and synchronized firing, whereas exosomes from MECP2-deficient hiPSC neural cultures lack this capability. These data indicate that exosomes carry signaling information required to regulate neural circuit development.