Compromised Hippocampal Neuroplasticity in the Interferon-α and Toll-like Receptor-3 Activation-Induced Mouse Depression Model

• DOI: 10.1007/s12035-020-01927-0
• Publication Date: 2020-06-05T08:06:00Z
• Authors: Eduardo H. Sanche...; Santiago Camblor-...; Luiza Martins Nas...; Egor Dzyubenko; Michael Fleischer; Tayana Silva de C...; Linda-Isabell Sch...; Markus Leo; Tim Hagenacker; Arne Herring; Kathy Keyvani; Sujoy Bera; Natalia Kononenko; Christoph Kleinsc...; Dirk M. Hermann
• Keywords: Neurons; 0301 basic medicine; 0303 health sciences; Neuronal Plasticity; Depression; Medizin; Interferon-alpha; Hippocampus; Article; Toll-Like Receptor 3; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Poly I-C; Patch clamp recording ; Dendritic plasticity ; Neurons/metabolism [MeSH] ; Depression/physiopathology [MeSH] ; Synaptic plasticity ; Toll-Like Receptor 3/metabolism [MeSH] ; Neuronal Plasticity/physiology [MeSH] ; Vesicular Glutamate Transport Protein 1/metabolism [MeSH] ; Animals [MeSH] ; Poly I-C [MeSH] ; Interferon-alpha [MeSH] ; Mice [MeSH] ; Article ; Neuronal depolarization ; Signal Transduction/physiology [MeSH] ; Disks Large Homolog 4 Protein/metabolism [MeSH] ; Neuronal plasticity ; Depression/chemically induced [MeSH] ; Hippocampus/physiopathology [MeSH] ; Disease Models, Animal [MeSH] ; Hippocampus/metabolism [MeSH] ; Major depressive disorder ; Depression/metabolism [MeSH]; Vesicular Glutamate Transport Protein 1; Animals; Disks Large Homolog 4 Protein; Signal Transduction

AbstractDisrupted neuronal plasticity due to subtle inflammation is considered to play a fundamental role in the pathogenesis of major depressive disorder. Interferon-α (IFN-α) potentiates immune responses against viral pathogens that induce toll-like receptor-3 (TLR3) activation but evokes severe major depressive disorder in humans by mechanisms that remain insufficiently described. By using a previously established mouse model of depression induced by combined delivery of IFN-α and polyinosinic:polycytidylic acid (poly(I:C)), a TLR3 agonist, we provide evidence that IFN-α and poly(I:C) reduce apical dendritic spine density in the hippocampal CA1 area ex vivo via mechanisms involving decreased TrkB signaling. In vitro, IFN-α and poly(I:C) treatments required neuronal activity to reduce dendritic spine density and TrkB signaling. The levels of presynaptic protein vesicular glutamate transporter (VGLUT)-1 and postsynaptic protein postsynaptic density-95 (PSD95) were specifically decreased, whereas the expression of both synaptic and extrasynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1 (AMPAR1) was increased by IFN-α and poly(I:C) delivery. Patch clamp recordings in primary hippocampal neurons revealed that morphological changes at the synapse induced by IFN-α and poly(I:C) costimulation were accompanied by an increased action potential threshold and action potential frequency, indicative of impaired neuronal excitability. Taken together, IFN-α and poly(I:C) delivery leads to structural and functional alterations at the synapse indicating that compromised neuroplasticity may play an integral role in the pathogenesis of immune response-induced depression.