Activation of the 5-HT7 receptor and MMP-9 signaling module in the hippocampal CA1 region is necessary for the development of depressive-like behavior
Monika Bijata, Ewa Bączyńska, Franziska E. Müller, Krystian Bijata, Julia Masternak, Adam Krzystyniak, Bernadeta Szewczyk, Marcin Siwiec, Svitlana Antoniuk, Matylda Roszkowska, Izabela Figiel, Marta Magnowska, Krzysztof H. Olszyński, Agnieszka D. Wardak, Adam S. Hogendorf, Błażej Ruszczycki, Nataliya Gorinski, Josephine Labus, Tomasz Stępień, Sylwia Tarka, Andrzej J. Bojarski, Krzysztof Tokarski, Robert K. Filipkowski, Evgeni Ponimaskin, Jakub Włodarczyk
Abstract
Major depressive disorder is a complex disease resulting from aberrant synaptic plasticity that may be caused by abnormal serotonergic signaling. Using a combination of behavioral, biochemical, and imaging methods, we analyze 5-HT7R/MMP-9 signaling and dendritic spine plasticity in the hippocampus in mice treated with the selective 5-HT7R agonist (LP-211) and in a model of chronic unpredictable stress (CUS)-induced depressive-like behavior. 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. Both pharmacological activation of 5-HT7R and modulation of its downstream effectors as a result of CUS lead to dendritic spine elongation and decreased spine density in this region. Overall, the 5-HT7R/MMP-9 pathway is specifically activated in the CA1 subregion of the hippocampus during chronic stress and is crucial for inducing depressive-like behavior.