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

Autor: Tayana Silva de Carvalho, Dirk M. Hermann, Santiago Camblor-Perujo, Kathy Keyvani, Tim Hagenacker, Eduardo H. Sanchez-Mendoza, Christoph Kleinschnitz, Sujoy Bera, Michael Fleischer, Linda-Isabell Schmitt, Natalia L. Kononenko, Luiza Martins Nascentes-Melo, Egor Dzyubenko, Markus Leo, Arne Herring
Rok vydání: 2020
Předmět:
Zdroj: Molecular Neurobiology
ISSN: 1559-1182
0893-7648
DOI: 10.1007/s12035-020-01927-0
Popis: Disrupted 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. Electronic supplementary material The online version of this article (10.1007/s12035-020-01927-0) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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