Flotillin-1 interacts with the serotonin transporter and modulates chronic corticosterone response.

Aberrant serotonergic neurotransmission in the brain is considered at the core of the pathophysiological mechanisms involved in neuropsychiatric disorders. Gene by environment interactions contribute to the development of depression and involve modulation of the availability and functional activity of the serotonin transporter (SERT). Using behavioral and in vivo electrophysiological approaches together with biochemical, molecular-biological and molecular imaging tools we establish Flotillin-1 (Flot1) as a novel protein interacting with SERT and demonstrate its involvement in the response to chronic corticosterone (CORT) treatment. We show that genetic Flot1 depletion augments chronic CORT-induced behavioral despair and describe concomitant alterations in the expression of SERT, activity of serotonergic neurons and alterations of the glucocorticoid receptor transport machinery. Hence, we propose a role for Flot1 as modulatory factor for the depressogenic consequences of chronic CORT exposure and suggest Flotillin-1-dependent regulation of SERT expression and activity of serotonergic neurotransmission at the core of the molecular mechanisms involved.

Long-term effects of maternal immune activation on depression-like behavior in the mouse.

Depression is a debilitating mental disease affecting a large population worldwide, the pathophysiological mechanisms of which remain incompletely understood. Prenatal infection and associated activation of the maternal immune system (MIA) are prominently related to an increased risk for the development of several psychiatric disorders including schizophrenia and autism in the offsprings. However, the role of MIA in the etiology of depression and its neurobiological basis are insufficiently investigated. Here we induced MIA in mice by challenge with polyinosinic:polycytidylic phosphate salt-a synthetic analog of double-stranded RNA, which enhances maternal levels of the cytokine interleukin-6 (IL-6)-and demonstrate a depression-like behavioral phenotype in adult offsprings. Adult offsprings additionally show deficits in cognition and hippocampal long-term potentiation (LTP) accompanied by disturbed proliferation of newborn cells in the dentate gyrus and compromised neuronal maturation and survival. The behavioral, neurogenic and functional deficiencies observed are associated with reduced hippocampal expression of vascular endothelial growth factor (VEGF)A-VEGFR2. IL-6-STAT3-dependent aberrant VEGFA-VEGFR2 signaling is proposed as neurobiological mechanism mediating the effects of MIA on the developing fetal brain and ensuing consequences in adulthood.