Social defeat stress develops depressive-like behaviors in mice by inducing inflammation both in the central nervous system and in the systemic circulation. Recent evidences have shown that the disruption of blood brain barrier leads to stress-induced behavioral alterations, suggesting that the integrity and deterioration of barriers surrounding the brain parenchyma is critical in stress-related pathophysiology. Although there has been emerging evidence showing the biochemical difference between the CSF of patients of depression and that of healthy controls, the effects of stress on the CSF system have rarely been studied. In the present study, we examined effects of social defeat stress on leptomeninges, which serve as barriers separating the brain parenchyma from the CSF and as regulators of immune reactions. We found an evidence of immediate phosphorylation of extracellular signal-regulated kinase (ERK) in the leptomeninges following a single episode of social defeat stress. This activation of ERK was diminished after repeated exposure to daily stress for 10 days. These evidences suggest that the leptomeninges are activated following an acute stress and diminish their responsiveness during the course of chronic stress.