Small Extracellular Vesicles Control Dendritic Spine Development through Regulation of HDAC2 Signaling

The release of small extracellular vesicles (sEVs) has recently been reported, but knowledge of their function in neuron development remains limited. Using LC-MS/MS, we found that sEVs released from developing cortical neurons in vitro obtained from mice of both sexes were enriched in cytoplasm, exosome, and protein-binding and DNA/RNA-binding pathways. The latter included HDAC2, which was of particular interest, because HDAC2 regulates spine development, and populations of neurons expressing different levels of HDAC2 co-exist in vivo during the period of spine growth. Here, we found that HDAC2 levels decrease in neurons as they acquire synapses and that sEVs from HDAC2-rich neurons regulate HDAC2 signaling in HDAC2-low neurons possibly through HDAC2 transfer. This regulation led to a transcriptional decrease in HDAC2 synaptic targets and the density of excitatory synapses. These data suggest that sEVs provide inductive cell-cell signaling that coordinates the development of dendritic spines via the activation of HDAC2-dependent transcriptional programs.SIGNIFICANCE STATEMENT A role of small extracellular vesicles (sEVs; also called exosomes) in neuronal development is of particular interest, because sEVs could provide a major signaling modality between developing neurons when synapses are not fully functional or immature. However, knowledge of sEVs on neuron, and more precisely spine development, is limited. We provide several lines of evidence that sEVs released from developing cortical neurons regulate the development of dendritic spines via the regulation of HDAC2 signaling. This paracrine communication is temporally restricted during development because of the age-dependent decrease in sEV release as neurons mature and acquire spines.