Choroid plexus modulates subventricular zone adult neurogenesis and olfaction through secretion of small extracellular vesicles

The choroid plexus (CP) in the brain ventricles secretes cerebrospinal fluid (CSF) that bathes the adjacent subventricular zone (SVZ). As the largest adult neurogenic region enriched with neural stem/progenitor cells (NSPCs), the SVZ supplies newborn neurons to the olfactory bulb (OB) for normal olfaction. This report depicts the presence of a CP-SVZ regulatory (CSR) axis, in which the CP regulates SVZ adult neurogenesis and olfaction via secretion of small extracellular vesicles (sEVs). The proposed CSR axis was supported by the evidence of (1) a direct effect of CP epithelial cells on the SVZ by in vivo transplantation and in vitro CP-SVZ co-culture assays, (2) differential OB neurogenesis following intracerebroventricular (ICV) infusion of sEVs derived from the CP of control or manganese (Mn)-poisoned mice, (3) progressively diminished SVZ adult neurogenesis after CP-selective inhibition of sEV secretion via AAV5-mediated SMPD3 knockdown, and (4) compromised olfactory performance following CP-selective SMPD3-knockdown. Collectively, our findings demonstrate the physiological, toxicological, and behavioral importance of this sEV-dependent CSR axis in the adult brain.