A dual role for interleukin-1 in hippocampal-dependent memory processes
Introduction
Interleukin-1 (IL-1) is a proinflammatory cytokine, produced by both glia and neurons within the brain. Signaling can be triggered by the attachment of either IL-1α or IL-1β to the type I receptor (IL-1R1), whereas IL-1 receptor antagonist (IL-1ra) blocks the effects of IL-1 (Dinarello, 1996). At pathophysiological levels, IL-1 can produce detrimental effects on memory. These effects are specific for the consolidation of memories that depend on the hippocampus, whereas hippocampal-independent memories are not altered (Rachal Pugh et al., 2001; Goshen and Yirmiya, 2007). Exogenous IL-1 also inhibits long-term potentiation (LTP) (Murray and Lynch, 1998; O’Connor and Coogan, 1999), a model system for the neural mechanism underlying memory, in several hippocampal pathways (Martin et al., 2000). However, recent evidence suggests that under some circumstances IL-1 may be required for the normal physiological regulation of hippocampal plasticity and memory processes: LTP in the hippocampus is accompanied by a long-lasting increase in IL-1β gene expression, and exposure to IL-1ra impairs the maintenance of LTP (Schneider et al., 1998). Furthermore, administration of IL-1ra impairs memory in the water-maze and passive-avoidance paradigms in rats, whereas relatively low doses of IL-1β improve avoidance memory (Yirmiya et al., 2002; Brennan et al., 2003; Song et al., 2003). The particularly high expression of IL-1, IL-1ra, and proteins belonging to the IL-1 receptor family in the hippocampus (Loddick et al., 1998) may underlie the effects of IL-1 within this structure.
Recently, we further demonstrated the importance of IL-1 signaling in hippocampal memory consolidation and neural plasticity by reporting that mice with targeted deletion of IL-1R1 (IL-1rKO) display a severely impaired hippocampal-dependent but normal hippocampal-independent memory. Furthermore, these mice demonstrate diminished short-term plasticity, and exhibit no LTP, both in vivo and in vitro (Avital et al., 2003). Since the deletion is permanent, these findings may be explained by the acute lack of IL-1 during memory consolidation and/or by abnormal brain development. The latter hypothesis may be clinically relevant since several studies in humans demonstrated that mutations in the IL-1 receptor accessory protein-like gene are involved in X-linked mental retardation (Carrie et al., 1999; Jin et al., 2000).
The data presented above indicates that on the one hand elevated IL-1 levels have detrimental effects on memory, but on the other hand low IL-1 doses can facilitate memory and blockade of IL-1 signaling is associated with impaired memory functioning. Together, the findings gathered so far suggest that the influence of IL-1 on memory follows an inverted U shaped pattern (Goshen and Yirmiya, 2007). According to this hypothesis, physiological levels of IL-1 are needed for memory formation; however, any deviation from the physiological range, either by excess elevation in IL-1 levels or by blockade of IL-1 signaling, results in impaired memory.
To further elucidate the role of IL-1 in memory processes, we investigated IL-1 gene expression following learning, and examined hippocampal-dependant memory in mice with transgenic over-expression of IL-1ra (IL-1raTG). Additionally, we investigated the involvement of IL-1 in the development of the neural substrate mediating hippocampal-dependent memory in mice that were chronically exposed to IL-1ra during prenatal brain development. Furthermore, we systematically tested the inverted U-shape hypothesis by intracerebroventricular (ICV) administration of different doses of IL-1β and IL-1ra following learning.
Section snippets
Subjects
Subjects were 2–4 month old male IL-1raTG mice and their C57BL/6 x CBA wild type (WT) controls (Stockholm University) and IL-1rKO mice and their 129/Sv X C57BL/6 WT controls (Jackson Laboratories, Bar Harbor). IL-1raTG mice have astrocyte-directed over-expression of the human IL-1ra gene under the control of the murine glial fibrillary acidic protein (GFAP) promoter, and are insensitive to the administration of exogenous IL-1 (Lundkvist et al., 1999; Shavit et al., 2005). IL-1rKO mice were
IL-1β gene expression is increased following learning
Fear conditioning induced a 2.8-fold increase in IL-1β gene expression in the hippocampus of WT mice 24 h, but not 1.5 or 4 h after contextual learning (Figure 1) (F(6,33)=5.322, p<0.001). Post hoc analyses revealed a significant difference between WT mice 24 h after conditioning to WT control mice (p<0.0001) and to WT mice that received only a shock at the same time (p<0.01). This increase cannot be attributed to the exposure to the stress caused by the electrical shock per se, but only to the
Discussion
In the present study we demonstrate in several converging strategies that IL-1 plays a critical role in hippocampal-dependent memory processes. First, we report that learning of a hippocampal-dependent task induces IL-1 gene expression in the hippocampus. Then we demonstrate that brain-specific blockade of IL-1 signaling in IL-1raTG mice specifically disrupts hippocampal-dependent memory. Furthermore we demonstrate, for the first time, the importance of IL-1 signaling during brain development,
Role of the funding source
This study was supported by grants from the Israel Ministry of Health (No. 2985), the Israel Science Foundation—The Revson Foundation (No. 799/03, to RY), and the Israel Foundations Trustees (No. 34/27, to IG).
All of the above had no further role in study design; in the collection, analysis and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.
Conflict of interest
None of the authors have any financial, personal or other conflict of interest that can influence this work.
Acknowledgments
We thank Prof. K. Iverfeldt for the IL-1raTG mice. This study was supported by grants from the Israel Ministry of Health (No. 2985), the Israel Science Foundation (Grant No. 295/07 to RY), and the Israel Foundations Trustees (No. 34/27, to IG). RY is a member of the Eric Roland Center for Neurodegenerative Diseases at the Hebrew University of Jerusalem.
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