The blood–brain barrier (BBB) is important in the normal functioning of the central nervous system. An altered BBB has been described in various neuropsychiatric disorders, including schizophrenia. However, the cellular and molecular mechanisms of such alterations remain unclear. Here, we investigate if BBB integrity is compromised in 22q11.2 deletion syndrome (also called DiGeorge syndrome), which is one of the validated genetic risk factors for schizophrenia. We utilized a set of human brain microvascular endothelial cells (HBMECs) derived from the induced pluripotent stem cell (iPSC) lines of patients with 22q11.2-deletion-syndrome-associated schizophrenia. We found that the solute permeability of the BBB formed from patient HBMECs increases by ~1.3–1.4-fold, while the trans-endothelial electrical resistance decreases to ~62% of the control values. Correspondingly, tight junction proteins and the endothelial glycocalyx that determine the integrity of the BBB are significantly disrupted. A transcriptome study also suggests that the transcriptional network related to the cell–cell junctions in the compromised BBB is substantially altered. An enrichment analysis further suggests that the genes within the altered gene expression network also contribute to neurodevelopmental disorders. Our findings suggest that neurovascular coupling can be targeted in developing novel therapeutical strategies for the treatment of 22q11.2 deletion syndrome.

On the surface of every mammalian cell, there is a matrix-like glycocalyx (GCX) consisting of proteoglycans and glycosaminoglycans (GAGs). Disruption of endothelial cell (EC) GCX by a vascular endothelial growth factor (VEGF, VEGF-A165), a tumor secretion, was found to be an early event in tumor cell (TC) metastasis across vascular barriers. However, how the TC secretion VEGF affects its own GCX is unknown. To investigate the VEGF effect on TC GCX and to elucidate the ultrastructural organization of EC and TC GCX and their alteration by VEGF, we employed super-resolution stochastic optical reconstruction microscopy to observe the spatio-chemical organizations of the heparan sulfate (HS) and hyaluronic acid (HA), two representative GAGs of GCX, on human cerebral microvascular endothelial cells (hCMEC) and malignant breast cancer cells MDA-MB-231 (MB231). We found that HS and HA have distinct organizations on hCMEC and MB231. Only HS of hCMEC is perpendicular to the cell surface, while HA of hCMEC as well as HS and HA of MB231 all lie in the same plane as the cell surface where they appear to weave into a 2D network covering the cell. We also found that VEGF significantly reduces the length and coverage of HS on hCMEC but does not change the thickness and coverage of HA on hCMEC. On the contrary, VEGF significantly enhances the coverage of HS and HA on MB231 although it does not alter the thickness. The differential effects of VEGF on the GCX of TC and that of EC may favor TC adhesion and transmigration across EC barriers for their metastasis.

Introduction: Transcranial direct current stimulation (tDCS) is a non‐invasive electrical stimulation investigated to treat a broad range of brain disorders and to enhance memory and cognition in healthy individuals. Our prior study has shown that tDCS with proper dosage can achieve non‐invasive and temporary increase in the blood‐brain barrier (BBB) permeability (P). To further investigate whether tDCS also increases the material transport in brain tissue, we employed high resolution multiphoton microscopy to collect the spreading images of fluorescently‐labeled solutes in the rat brain tissue after tDCS treatment. The effective solute diffusion coefficient in the brain tissue (D _eff ) was determined by using our previously developed method. D _eff is a quantitative indicator for solute transport in a medium. Methods: After 20 min 1 mA tDCS treatment, sodium fluorescein (MW 376), or FITC‐dextran 70k in 1% BSA mammalian Ringer was injected into the rat (SD, 250–300g) cerebral circulation via the ipsilateral carotid artery by a syringe pump at a constant rate of ~3 ml/min. Simultaneously, the 3‐D images of a post‐capillary vessel and its surrounding area in the rat brain tissue 100–200 mm below the pia mater were collected by laser scanning multiphoton microscopy with 820 nm excitation wavelength. The cerebral microvessel permeability (P) and the effective solute diffusion coefficient in the brain tissue D _eff were determined from the rate of dye spreading images. Specifically, D _eff was estimated by curve fitting the spatio‐temporal solute concentration (fluorescence intensity) distribution by using an unsteady diffusion transport model. Results and Discussion: It was found that in 5–10 min post 20 min–1mA tDCS, D _eff /D _free increases from 0.45 to 0.50 for sodium fluorescein (n=5) and from 0.11 to 0.25 for dextran 70k (n=6), all the increased D _eff returned to the control level in 25–30 min post tDCS. tDCS indeed transiently makes the brain tissue less restrictive to solute transport, especially for larger solutes. Conclusions: tDCS not only transiently increases the BBB permeability but also enhances the solute transport in brain tissue. Support or Funding Information: Supported by NIH RO1 NS101362‐01