Abstract
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.
Highlights
30 to 50% of patients suffering from chronic hepatitis C virus (HCV) who are treated with IFN-α develop severe depression along with confusion states, paranoia, and suicidal ideation [1, 2], which is in many cases a cause of therapy discontinuation [1, 3]
We previously showed that IFN-α and toll-like receptor-3 (TLR3) activation by poly(I:C) regulates the neuronal expression of a broad set of depression-associated genes in the hippocampus and prefrontal cortex of mice that were found to be regulated in IFN-α-treated depressed patients and which correlated with depressive behavior in mice [1, 4]
By combining ex vivo and in vitro studies, we report here morphological, biochemical, and electrophysiological correlates of reduced dendritic and synaptic plasticity in the CA1 region of the hippocampus and dentate gyrus in a model of IFN-α and TLR3 activation-induced depression in mice which we previously characterized on the behavioral level [4]
Summary
30 to 50% of patients suffering from chronic hepatitis C virus (HCV) who are treated with IFN-α develop severe depression along with confusion states, paranoia, and suicidal ideation [1, 2], which is in many cases a cause of therapy discontinuation [1, 3]. Apart from the inflammatory response induced by any infectious viral organism, double-stranded RNA viruses induce pronounced TLR3 activation. We previously showed that IFN-α and TLR3 activation by poly(I:C) regulates the neuronal expression of a broad set of depression-associated genes in the hippocampus and prefrontal cortex of mice that were found to be regulated in IFN-α-treated depressed patients and which correlated with depressive behavior in mice [1, 4]. Mol Neurobiol (2020) 57:3171–3182 showed that combined delivery of IFN-α and poly(I:C) induced localized inflammatory responses within the prefrontal cortex and hippocampus [4]. The regulation of growth, maturation, or pruning of dendritic spines and synaptic contacts and functional organization of neuronal networks is essential for the establishment of physiological behaviors [3, 5]. Compromised neuronal plasticity and communication in response to neurotransmitter release may contribute to depression pathogenesis
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