In the central nervous system (CNS), neurons, glia and vascular cells including endothelial cells, vascular smooth muscle cells and pericytes communicate with each other by rapid and direct exchange of small signaling molecules through gap junctions, multi-step signaling through receptors and channels, and exosomes, for long-range communication with distant targets [1]. In contrast to peripheral organs with highly permeable capillaries [2], brain capillaries, a site of the blood-brain barrier (BBB) in vivo, prevent entry of blood-derived toxic substances and pathogens into the brain [3, 4]. The BBB regulates transport of oxygen, energy metabolites, nutrients and regulatory molecules from blood to brain, and clears metabolic waste products from brain into circulation [1]. Brain endothelial cells are connected by tight and adherens junctions, which forms anatomical BBB [1]. Brain endothelium expresses thousands of different transporters and receptors, and is endowed with perivascular cells—pericytes that are separated from endothelium by the basement membrane. Astrocyte end-feet cover most of the vessel wall allowing direct communications between astrocytes and pericytes, from one end, and astrocytes and endothelium, from the other end [1]. Neural microenvironment plays a key role in BBB development via Wnt and Sonic Hedgehog (Shh) signaling pathways [1]. Neuronal activity influences cerebrovascular pattern [5] and transport across the BBB of substrates such as serum insulin-like growth factor-1 [6]. However, the role of exosomes in regulating BBB integrity and functions is poorly understood. Exosomes are 30-100 nm doublemembrane extracellular vesicles produced by nearly every cell type. They are generated mainly from reverse budding of multivesicular bodies, and are enriched in signaling proteins and lipids of parental cells. Exosomes play an important role in neuron-glia communication and regulation of synaptic plasticity [7]. They carry and deliver pathogenic peptides, such as amyloid-β, prion, α-synuclein and tau [7], and play a role in communication across the BBB between periphery and CNS during systemic inflammation [8]. Exosomes also carry RNAs including microRNAs. MicroRNAs are small non-coding RNAs with~ 22 nucleotides capable of silencing gene expression via the RNA-induced silencing complex. In the CNS, microRNAs have been shown to not only contribute to gene regulation during development, but also to remodeling of neural circuits in adulthood. MicroRNAs have been associated with pathogenesis of many CNS disorders [9]. First known for their essential roles in cell-autonomous regulation of gene expression, the microRNA-dependent exosomal signaling is currently being recognized as an intercellular route in regulating gene expression in distant cells. For instance, in response to peripheral inflammation, exosomes from hematopoietic cells contribute to longrange RNA-based communications with Purkinje neurons in the brain across the BBB [10].

In a recent paper in Cell Research, Xu and colleagues [11] used zebrafish as a model system to examine the function of miR-132, a microRNA predominantly expressed in neurons. By antagonizing miR-132 with morpholino antisense oligonucleotides, they surprisingly found that zebrafish larvae with inactivated miR-132 (miR-132 morphants) exhibited severe intracranial hemorrhage and impaired BBB integrity, as shown by extravasation of red blood cells and brain accumulation of exogenous circulating tracers. This finding was confirmed by a genomic editing using Cas9 (CRISPR associated protein 9) and miR-132-specific guide RNAs to disrupt the …