Choroid Plexus Modulates Subventricular Zone Adult Neurogenesis and Olfaction Through Secretion of Small Extracellular Vesicles

The choroid plexus (CP) in brain ventricles secrete cerebrospinal fluid (CSF) that bathes the adjacent subventricular zone (SVZ); the latter is the largest adult neurogenic region that enriches neural stem/progenitor cells (NSPCs) and supplies newborn neurons to the olfactory bulb (OB) for normal olfaction. We discovered the presence of a CP-SVZ regulatory (CSR) axis in which the CP regulates SVZ adult neurogenesis and olfaction by secreting small extracellular vesicles (sEVs). The proposed CSR axis was supported by 1) differential neurogenesis outcomes in the OB when animals treated with intracerebroventricular (ICV) infusion of sEVs collected from the CP of normal or manganese (Mn)-poisoned mice, 2) progressively diminished SVZ adult neurogenesis in mice following the inhibition of CP-selective sEV secretion by AAV5-medaited SMPD3 knockdown, and 3) compromised olfactory performance in CP-selective SMPD3-knockdown mice. Collectively, our findings demonstrate the physiological, toxicological, and behavioral importance of this sEV-dependent CSR axis in adult brains.