Major depessive disorder (MDD) is linked to increased levels of circulating pro-inflammatory cytokines, such as interleukin 6 (IL-6). Among mice subjected to chronic social defeat stress (a rodent model of depression), the expression of the tight junction protein claudin-5 (CLDN5) at the blood–brain barrier (BBB) was reduced in the nucleus accumbens (NAc) in animals with greater susceptibility to depression-like behaviour; people with MDD also showed reduced CLDN5 mRNA levels in the NAc. Knock-down of CLDN5 in mice increased BBB permeability and brain IL-6 levels, and induced depression-like behaviours, suggesting a role for CLDN5 in MDD.