Collectively, these data show that restoration of p11 expression in ependymal cells is sufficient for the reversal of the decreased CSF flow and depressive behaviors induced by chronic stress and genetically manipulated mice with ependymal cells or constitutive deletion of p11, indicating that p11 is a key molecular determinant for ependymal cells in the regulation of CSF flow and depression. Here, S100A10 is linked to major depressive disorder.