IFN-γ differentially modulates memory-related processes under basal and chronic stressor conditions

Abstract

Cytokines are inflammatory messengers that orchestrate the brain’s response to immunological challenges, as well as possibly even toxic and psychological insults. We previously reported that genetic ablation of the pro-inflammatory cytokine, interferon-gamma (IFN-γ), attenuated some of the corticosteroid, cytokine, and limbic dopaminergic variations induced by 6 weeks of exposure to an unpredictable psychologically relevant stressor. Presently, we sought to determine whether a lack of IFN-γ would likewise modify the impact of chronic stress on hippocampus-dependent memory function and related neurotransmitter and neurotrophin signaling systems. As predicted, chronic stress impaired spatial recognition memory (Y-maze task) in the wild-type animals. In contrast, though the IFN-γ knockouts (KOs) showed memory disturbances in the basal state, under conditions of chronic stress these mice actually exhibited facilitated memory performance. Paralleling these findings, while overall the KOs displayed altered noradrenergic and/or serotonergic activity in the hippocampus and locus coeruleus, norepinephrine utilization in both of these memory-related brain regions was selectively increased among the chronically stressed KOs. However, contrary to our expectations, neither IFN-γ deletion nor chronic stressor exposure significantly affected nucleus accumbens dopaminergic neurotransmission or hippocampal brain-derived neurotrophic factor protein expression. These findings add to a growing body of evidence implicating cytokines in the often differential regulation of neurobehavioral processes in health and disease. Whereas in the basal state IFN-γ appears to be involved in sustaining memory function and the activity of related brain monoamine systems, in the face of ongoing psychologically relevant stress the cytokine may, in fact, act to restrict potentially adaptive central noradrenergic and spatial memory responses.

Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons

“…Several recent studies have suggested that the IFN-γ acts as a negative regulator of hippocampal functions. For example, the IFN-γ-deficient mice have shown impaired spatial memory, increased neurogenesis, dendritic arborizations, and probability of pre-synaptic neurotransmitter release in the hippocampal sub-regions (Litteljohn et al, 2014;Monteiro et al, 2016). Furthermore, intracerebroventricular injection of IFN-γ impairs the induction of long-term potentiation (LTP), an electrophysiological correlate of learning and memory, in hippocampal slices of rats (Maher T et al, 2006).…”

Cytokines and cytokine networks target neurons to modulate long-term potentiation

“…, the maintenance of LTP in the hippocampus is blocked by the IL-1 receptor antagonist, IL-1RA (53)). IFNγ, a molecule crucial for the immune response against viruses, is another inflammatory cytokine that can facilitate LTP and memory (54, 55). According to a recent report using IFNγ-deficient mice, endogenous IFNγ signaling can facilitate LTP by blocking GABA-mediated inhibition in the hippocampus (55).…”

The promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 primate-specific endogenous retrovirus: an evolutionary connection between immunity and cognition

“…Indeed, our data indicates that non-inherited forms of ID might result from alterations of the immune/MER41/cognition pathway. Such a dysfunction may be induced by the untimely or quantitatively inappropriate exposure of neurons to specific cytokines, notably IL-6 or IFN, which physiologically shape neurotransmission (Baier et al, 2009;Chourbaji et al, 2006;Gruol, 2015;Litteljohn et al, 2014;Victório et al, 2010) and are possibly involved in the immune/MER41/cognition pathway.…”

“…Interferon gamma (IFN), the prototypical T Helper 1 (TH1) cytokine, is a T-cell derived proinflammatory molecule exerting several effects on innate immune cells and others on nonimmune cells including neurons (Litteljohn et al, 2014). Specifically, IFN was recently shown to be a social behavior regulator and to shape neuronal connectivity in rodents (Filiano et al, 2016).…”