Interleukin-1β-induced memory reconsolidation impairment is mediated by a reduction in glutamate release and zif268 expression and α-melanocyte-stimulating hormone prevented these effects

Highlights

• IL-1β impairs memory reconsolidation through a decrease in glutamate release.

• IL-1β reduces p-ERK2 levels and zif268 expression after reconsolidation of memory.

• α-MSH prevent molecular changes induced by IL-1β during reconsolidation.

Abstract

The immune system is an important modulator of learning, memory and neural plasticity. Interleukin 1β (IL-1β), a pro-inflammatory cytokine, significantly affects several cognitive processes. Previous studies by our group have demonstrated that intrahippocampal administration of IL-1β impairs reconsolidation of contextual fear memory. This effect was reversed by the melanocortin alpha-melanocyte-stimulating hormone (α-MSH). The mechanisms underlying the effect of IL-1β on memory reconsolidation have not yet been established. Therefore, we examined the effect of IL-1β on glutamate release, ERK phosphorylation and the activation of the transcription factor zinc finger- 268 (zif268) during reconsolidation. Our results demonstrated that IL-1β induced a significant decrease of glutamate release after reactivation of the fear memory and this effect was related to calcium concentration in hippocampal synaptosomes. IL-1β also reduced ERK phosphorylation and zif268 expression in the hippocampus. Central administration of α-MSH prevented the decrease in glutamate release, ERK phosphorylation and zif268 expression induced by IL-1β. Our results establish possible mechanisms involved in the detrimental effect of IL-1β on memory reconsolidation and also indicate that α-MSH may exert a beneficial modulatory role in preventing IL-1β effects.

Introduction

It is now well established that the immune system, and in particular the pro-inflammatory cytokine interleukin-1β (IL-1β), can modulate brain functioning. When the immune system is activated by infection, injury or chronic inflammatory conditions, as well as by severe or chronic stressful conditions, glia and/or some neuron populations can secrete high levels of pro-inflammatory cytokines that produce detrimental effects on memory, neural plasticity and neurogenesis. Also, pathologies with increased peripheral levels of cytokines such as autoimmune diseases and after administration for therapeutic purposes, are associated with cognitive disturbance in humans, particularly with deficits in learning and memory (Yirmiya and Goshen, 2011).

New memories are transformed from an initially labile short-term memory state into a stable long-term memory over time by a process called consolidation (McGaugh, 2000). However, consolidated memories may again become labile and susceptible to disruption when reactivated. Therefore, retrieval of a previously consolidated memory may induce a new labile period during which the memory can be modified and this may require an active process to stabilize the memory again. This process has been called reconsolidation (Nader et al., 2000, Dudai, 2006). Its adaptive purpose might be to permit the integration of new information present at the time of retrieval into an updated memory. However, the reconsolidation process is not a simple reiteration of consolidation (Tronson and Taylor, 2007). Although both processes require de novo protein synthesis for memory persistence (Nader et al., 2000), it has been reported that the molecular mechanisms underlying these two processes within the hippocampus are different (Lee et al., 2004). Thus, brain-derived neurotrophic factor (BDNF) is selectively required for memory consolidation, whereas the transcription factor zinc finger-268 (zif-268) is selectively required for reconsolidation of contextual fear memory (Lee et al., 2004). Moreover, zif-268 is activated in the hippocampus by retrieval of a contextual fear memory (Hall et al., 2001). It has been proposed that signaling pathways activated during the reconsolidation process are induced by glutamate release. Glutamate participation was established using different antagonists of AMPA or NMDA receptors in different species and paradigms (Pedreira et al., 2002, Suzuki et al., 2004) Other studies showed that reconsolidation requires phosphorylation of GluR1 glutamate receptor subunits (Monfils et al., 2009). Stimulation of glutamate receptors produces activation of different kinases. Two of them, the extracellular signal-regulated kinase (ERK) and protein kinase A (PKA) have attracted particular interest due their well-established roles in reconsolidation.

The effect of IL-1β in memory consolidation has been extensively studied. It has been proposed that basal IL-1β levels are needed for memory consolidation, but that increased IL-1β levels induced by immune, physical, psychological challenge or even blockade of IL-1β signaling result in memory impairment (Pugh et al., 1998, Barrientos et al., 2002, Yirmiya and Goshen, 2011). However, recent studies in IL-1RI^−/− mice showed no significant impairment in hippocampal dependent memory and learning, which may lead to re-evaluation of the role of endogenous IL-1 in hippocampal function (Murray et al., 2013).

We previously demonstrated that IL-1β interferes with contextual fear memory consolidation (Gonzalez et al., 2009, Gonzalez et al., 2013). The effects of immune activation or cytokines on memory reconsolidation have been studied far less (Machado et al., 2010, Kranjac et al., 2012). We recently shown that IL-1β infused directly into the hippocampus may also have a detrimental effect on reconsolidation of contextual fear memory (Machado et al., 2010). In other experimental models IL-1β was shown to modify some of the signaling molecules critically involved in memory reconsolidation. In these reports, IL-1β reduced glutamate release during LTP (Kelly et al., 2003), decreased ERK phosphorylation during memory consolidation (Gonzalez et al., 2013) and in activated microglia in culture (Saud et al., 2005) and also decreased zif268 expression in human epidermal keratinocytes (Lukiw et al., 1998). However, the molecular mechanism involved in the effect of IL-1β on memory reconsolidation has not yet been established.

Melanocortins, endogenous peptides produced by post-translational processing of pro-opiomelanocortin (POMC), have been implicated in multiple processes in the central nervous system (CNS) including immunomodulatory effects (Catania et al., 2010, Caruso et al., 2014). Melanocortins exert actions through five different G protein-coupled receptors (MC1/MC5). MC3 and MC4 receptors are predominantly expressed throughout the CNS including the hippocampus (Muceniece and Dambrova, 2010). α-MSH through activation of MC4R reverses the effect of IL-1β on consolidation (Gonzalez et al., 2009) and reconsolidation of a contextual fear memory (Machado et al., 2010). It has been reported that α-MSH could produce activation of ERK pathway in different experimental models, in vivo (Sutton et al., 2005) in CHO-K1 cells (Vongs et al., 2004), and in astrocytes and microglia (Carniglia et al., 2013). α-MSH can also increase zif268 expression in hippocampus, improving learning and memory after cerebral ischemia (Giuliani et al., 2009). Moreover, α-MSH induced over-expression of zif268 and improved cognitive functions in an Alzheimer’s disease model through MC4R activation (Giuliani et al., 2014). Therefore, the molecular mechanism involved in memory reconsolidation could be modified by IL-1β and/or α-MSH to produce their effects.

The objective of this study was to identify molecular mechanisms induced by intrahippocampal administration of IL-1β that might lead to impairment of memory reconsolidation and also to evaluate the modulatory role of α-MSH.

Pro-inflammatory cytokines mediate cognitive impairments associated with several neuropsychiatric diseases and neurodegenerative disorders. Consequently it is of relevant importance to study signaling pathways involved in the detrimental effects of cytokines on memory processes. Also importantly, the immunomodulatory effects of melanocortins propose them as potentially useful in the treatment of undesirable central effects of cytokines.