Role of IL-1 Signaling in Controlling Synaptic Function

Mantovani, Cristina (2019). Role of IL-1 Signaling in Controlling Synaptic Function. PhD thesis The Open University.



Although several studies demonstrate that inflammation contributes to neurodegenerative and psychiatric disorders, the physiological functions of immune molecules in synapse formation and functionality are not completely known. Interleukin-1β (IL-1β) has been described as one of the main pro-inflammatory cytokines involved in several neurological disorders. IL-1β is produced by many types of cells, including immune cells in the periphery, as well as glia and neurons within the brain [Dinarello CA, 1996]. The ability of IL-1β to influence cellular functions depends on the expression of the appropriate receptor and the activation of specific intracellular signaling pathways. Two receptors for IL-1β have been identified, but only the type 1 receptor (IL-1R1) is signal transducing [Sims JE et al., 1993]. IL-1R1 is expressed on central nervous system (CNS) glia (astrocytes and microglia), particularly after injury [Friedman WJ, 2001], and also on specific populations of CNS neurons, including hippocampal pyramidal neurons [Yabuuchi K et al., 1994; Ericsson A et al., 1995; Friedman WJ, 2001]. IL-1β elicits distinct functional effects in these CNS cell types, regulating the production of inflammatory cytokines in glia and influencing synaptic function of hippocampal neurons, affecting long-term potentiation (LTP) [Katsuki H et al., 1990; Bellinger FP et al., 1993; Murray CA and Lynch MA, 1998; Kelly A et al., 2001]. Previous studies reported that impaired Interleukin-1 signalling is associated with deficits in hippocampal memory processes and neural plasticity [Avital A et al., 2003] and that IL-1R is essential for the activation of microglia and the induction of proinflammatory mediators in response to brain injury [Basu A et al., 2002].

Despite the well-established role of this cytokine in different brain diseases, its putative physiological function during normal brain development is not completely known. The aim of this study is to clarify if, and how, Interleukin-1 signalling participates in the maintainance of synapse homeostasis in the CNS. In order to study how endogenous IL-1β signaling may alter normal brain development and functionality, we took advantage of an IL-1 type 1 receptor (IL-1R1) knock-out mouse model, where the IL-1 signaling is genetically blocked.

Our results show that lack of IL-1R affects excitatory inputs in vivo, leading to a significant increase in the expression of excitatory synaptic markers in both cortex and hippocampus. In line with this evidence, Golgi-cox staining of fixed brain slices revealed a significantly higher spine density in CA1 pyramidal neurons of IL-1R-/- hippocampi. Consistently, electrophysiological recordings from hippocampal acute slices demonstrated enhanced frequency and amplitude of miniature excitatory postsynaptic currents in IL-1R-/- mice, confirming the functional potentiation of the excitatory signalling in the hippocampus of knock-out mice. We also observed a transiently increased number of parvalbumin-positive GABAergic interneurons in the hippocampal CA1 region of P30 IL-1R-deficient mice (although, this increased number is completely rescued in older mice), suggesting a possible role of IL-1 signalling in the control of the GABAergic system during early stages in life. These data demonstrate a key role of the IL-1 receptor in controlling excitatory and inhibitory network refinement and strengthening during brain development. However, this process was not observed in primary culture of hippocampal neurons established from IL-1R-/- mice, thus suggesting a non-cell-autonomous effect. In line with this observation, we observed a transient increase in microglia number in IL-1R-/- mice during the first weeks of postnatal life (a critical time point for synapse maturation and elimination), although completely recovered in older mice. Moreover, using mixed co-cultures, we found that IL-1R-/- microglia cells were less effective in promoting synaptic elimination when compared to WT microglia cells.

In conclusion, IL-1R signaling seems to play a key role in modulating glutamatergic and GABAergic synapses and its absence leads to a general and long-lasting potentiation of excitatory inputs. Since microglia contribute to synaptic pruning and network refinement in the first postnatal weeks, the alteration in microglia-mediated synapse pruning in IL-1R-/- mice may be involved in this process, eventually leading to short-term effects on postnatal synaptic maturation and long-term effects on adult brain networks.

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