Dataset Information

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

ABSTRACT: Disrupted neuronal plasticity due to subtle inflammation is considered to play a fundamental role in the pathogenesis of major depressive disorder. Interferon-? (IFN-?) 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-? and polyinosinic:polycytidylic acid (poly(I:C)), a TLR3 agonist, we provide evidence that IFN-? 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-? 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 ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1 (AMPAR1) was increased by IFN-? and poly(I:C) delivery. Patch clamp recordings in primary hippocampal neurons revealed that morphological changes at the synapse induced by IFN-? 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-? 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.

SUBMITTER: Sanchez-Mendoza EH

PROVIDER: S-EPMC7320059 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Sanchez-Mendoza Eduardo H EH Camblor-Perujo Santiago S Martins Nascentes-Melo Luiza L Dzyubenko Egor E Fleischer Michael M Silva de Carvalho Tayana T Schmitt Linda-Isabell LI Leo Markus M Hagenacker Tim T Herring Arne A Keyvani Kathy K Bera Sujoy S Kononenko Natalia N Kleinschnitz Christoph C Hermann Dirk M DM

Molecular neurobiology 20200605 7

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:polycy ...[more]

PMID: 32504419

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Project description:BackgroundToll-like receptors (TLRs) are among the first-line sentinels for immune detection and responsiveness to pathogens. The TLR2 subfamily of TLRs (TLR1, TLR2, TLR6) form heterodimers with each other and are thus able to recognize a broad range of components from several microbes such as yeast, Gram-positive bacteria and protozoa. Until now, TLR2 activation by bacterial ligands has long been associated with pro-inflammatory cytokines but not type I interferon responses.Methodology/principal findingsUsing a variety of transgenic mice, here we provide in vivo and in vitro data showing that TLR2 activation does in fact induce interferon-beta and that this occurs via MyD88-IRF1 and -IRF7 pathways. Interestingly, by microscopy we demonstrate that although a cell surface receptor, TLR2 dependent induction of type I interferons occurs in endolysosomal compartments where it is translocated to upon ligand engagement. Furthermore, we could show that blocking receptor internalization or endolysosomal acidification inhibits the ability of TLR2 to trigger the induction type I interferon but not pro-inflammatory responses.Conclusion/significanceThe results indicate that TLR2 activation induces pro-inflammatory and type I interferon responses from distinct subcellular sites: the plasma membrane and endolysosomal compartments respectively. Apart from identifying and characterizing a novel pathway for induction of type I interferons, the present study offers new insights into how TLR signaling discriminates and regulates the nature of responses to be elicited against extracellular and endocytosed microbes. These findings may also have clinical implication. Excessive production of pro-inflammatory cytokines and type I IFNs following activation of TLRs is a central pathologic event in several hyper-inflammatory conditions. The discovery that the induction of pro-inflammatory and type I IFN responses can be uncoupled through pharmacological manipulation of endolysosomal acidification suggests new avenues for potential therapeutic intervention against inflammations and sepsis.

Project description:Single sub-anesthetic doses of ketamine can exacerbate the symptoms of patients diagnosed with schizophrenia, yet similar ketamine treatments rapidly reduce depressive symptoms in major depression. Acute doses of the atypical antipsychotic drug clozapine have also been shown to counteract ketamine-induced psychotic effects. In the interest of understanding whether these drug effects could be modeled with alterations in neuroplasticity, we examined the impact of acutely-administered ketamine and clozapine on in vivo long-term potentiation (LTP) in the rat's hippocampus-to-prefrontal cortex (H-PFC) pathway. We found that a low dose of ketamine depressed H-PFC LTP, whereas animals that were co-administrated the two drugs displayed LTP that was similar to a saline-treated control. To address which signaling molecules might mediate such effects, we also examined phosphorylation and total protein levels of GSK3β, GluA1, TrkB, ERK, and mTOR in prefrontal and hippocampal sub-regions. Among the statistically significant effects that were detected (a) both ketamine and clozapine increased the phosphorylation of Ser9-GSK3β throughout the prefrontal cortex and of Ser2481-mTOR in the dorsal hippocampus (DH), (b) clozapine increased the phosphorylation of Ser831-GluA1 throughout the prefrontal cortex and of Ser845-GluA1 in the ventral hippocampus, (c) ketamine treatment increased the phosphorylation of Thr202/Tyr204-ERK in the medial PFC (mPFC), and (d) clozapine treatment was associated with decreases in the phosphorylation of Tyr705-TrkB in the DH and of Try816-TrkB in the mPFC. Further analyses involving phosphorylation effect sizes also suggested Ser831-GluA1 in the PFC displayed the highest degree of clozapine-responsivity relative to ketamine. These results provide evidence for how ketamine and clozapine treatments affect neuroplasticity and signaling pathways in the stress-sensitive H-PFC network. They also demonstrate the potential relevance of H-PFC pathway neuroplasticity for modeling ketamine-clozapine interactions in regards to psychosis.

Dataset Information

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

Publications

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

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