The blood–brain barrier (BBB) prevents many substances in the blood from penetrating the brain. To do so, tight junctions (TJs) form between adjacent brain endothelial cells. Occludins, junctional adhesion molecules (JAMs) and claudins are involved in TJ formation. Previous studies have shown that TJs can form without occludin, and that JAMs associate with TJs but are not a constituent of them. Claudin on the other hand comprises the backbone of TJs. Reporting in the Journal of Cell Biology, Nitta et al. found that in claudin-5 (Cldn5)-deficient mice the BBB is loosened in a size-selective manner.

Cldn5 knockout mice seem to have morphologically intact brain blood vessels. But is the barrier function of TJs affected in these mice? To answer this question, wild-type and Cldn5−/− embryos were injected with a tracer previously used to evaluate TJ permeability. In wild-type embryos the tracer was specifically excluded from the central nervous system and was retained in the blood vessels. By contrast, in Cldn5−/− mice the brain and spinal cord showed the presence of tracer throughout the brain parenchyma.

So, the BBB was severely affected in Cldn5−/− mice. However, on examination of these mice, the authors found no signs of oedema, nor did they find any leakage of serum albumin proteins from blood vessels to the Cldn5−/− brain, indicating that the architecture of the BBB had not been completely disrupted. In light of this, the authors hypothesize that the BBB is loosened in a size-selective manner in Cldn5−/− mice. Indeed, when a mixture of dextran (10 kDa) and fluorescent nuclear stain (562 Da) was perfused through the heart of Cldn5−/− mice, not only did the nuclei of endothelial cells, but also the surrounding neurons became fluorescent, whereas the much larger dextran was only detected in blood vessels.

The permeability and lack of oedema in Cldn5−/− mice is particularly important from the standpoint of drug delivery. Cld5 might offer a way in which to manipulate the passage of small drugs to cross the BBB without the complete breakdown of the barrier. The next step will be to generate conditional Cldn5−/− mice in which only Cldn5 present in the brain endothelial cells is disrupted, rather than general Cldn5 knockout mice, which die 10 hours after birth.