Seminarium Zakładu Biofizyki

Although many individuals experience stressful events and are exposed to trauma during life, most do not develop psychiatric illnesses such as Major Depressive Disorder (MDD) – these individuals are stress-resilient. Previously, we showed a causal link between serotonin receptor (5-HT7R) - mediated signaling and extracellular cleavage of the cell adhesion molecule (CD44), by matrix metalloproteinase 9 (MMP-9), which in turn engages small GTPase (Cdc42) to regulate structural and functional plasticity of dendritic spines (Bijata et al., 2017, Cell Rep.). Our recent results suggest that the resilience phenomenon is associated with the inactivation of postsynaptic 5-HT7R-mediated signaling. In support of this view, we show that acute 5-HT7R activation induces depressive-like behavior in mice in an MMP-9-dependent manner and that post mortem brain samples from human individuals with depression reveal increased MMP-9 enzymatic activity in the hippocampus, while selective inhibition of 5-HT7R promotes stress resilience. The activation of 5-HT7R correlates with dendritic spine abnormalities in the CA1 region of the hippocampus via the activation of the 5-HT7R/MMP-9/Cdc42 signaling pathway. Concomitantly, this signaling pathway is activated in animal model of depression induced by chronic stress, while selectively knocking down the expression of the Htr7 gene in the CA1 hippocampal subregion of C57BL/6J mice promotes resilience in the same chronic stress model (Bijata et al., 2022, Cell Rep.). Taken together, our results indicate a possible role of 5-HT7R downstream signaling proteins in aberrant synaptic plasticity, implicating the 5‑HT7R/MMP-9/Cdc42 signaling module as a possible target for the treatment of stress related disorders.