Caroline Menard 1 , Madeline L. Pfau 1 , Georgia E. Hodes 1 , Veronika Kana 2 , Victoria X. Wang 3 , Sylvain Bouchard 1 , Aki Takahashi 1 , 4 , Meghan E. Flanigan 1 , Hossein Aleyasin 1 , Katherine B. LeClair 1 , William G. Janssen 1 , Benoit Labonté 1 , Eric M. Parise 1 , Zachary S. Lorsch 1 , Sam A. Golden 1 , Mitra Heshmati 1 , Carol Tamminga 5 , Gustavo Turecki 6 , Matthew Campbell 7 , Zahi Fayad 3 , Cheuk Ying Tang 3 , Miriam Merad 2 , Scott J. Russo 1
13 November 2017
Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood-brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of endothelial cell tight junction protein claudin-5 (cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 down-regulation was sufficient to induce depression-like behaviors following subthreshold social stress while chronic antidepressant treatment rescued cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or AAV-shRNA- cldn5-injected mice caused infiltration of peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein cldn5, promoting peripheral IL-6 passage across the BBB and depression.