Abstract
BackgroundBrain inflammation including increases in inflammatory cytokines such as IL-1β is widely believed to contribute to the pathophysiology of Alzheimer’s disease. Although IL-1β-induced impairments in long-term potentiation (LTP) in acute hippocampal slices and memory functions in vivo have been well documented, the neuron-specific molecular mechanisms of IL-1β-mediated impairments of LTP and memory remain unclear.MethodsThis study uses an in vitro approach in primary hippocampal neurons to evaluate the effect of IL-1β on chemical LTP (cLTP)-induced structural plasticity and signaling.ResultsWe found that IL-1β reduces both the surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 and the spine growth following cLTP. These effects of IL-1β were mediated by impairing actin polymerization during cLTP, as IL-1β decreased the cLTP-induced formation of F-actin, and the effect of IL-1β on cLTP-induced surface expression of GluA1 can be mimicked by latrunculin, a toxin that disrupts dynamics of actin filaments, and can be prevented by jasplakinolide, a cell-permeable peptide that stabilizes F-actin. Moreover, live-cell imaging demonstrated that IL-1β decreased the stability of the actin cytoskeleton in spines, which is required for LTP consolidation. We further examined the role of sphingolipid signaling in the IL-1β-mediated impairment of spine plasticity and found that both the neutral sphingomyelinase inhibitor GW4869 and the inhibitor of Src kinase PP2 attenuated the IL-1β-mediated suppression of cLTP-induced surface expression of GluA1 and actin polymerization.ConclusionsThese findings support a mechanism by which IL-1β, via the sphingomyelinase/ceramide/Src pathway, impairs structural spine remodeling essential for LTP consolidation and memory.
Highlights
Brain inflammation including increases in inflammatory cytokines such as IL-1β is widely believed to contribute to the pathophysiology of Alzheimer’s disease
IL-1β decreased chemical LTP (cLTP)-induced GluA1surface expression and spine growth We first tested the possibility that IL-1β impairs GluA1containing AMPA receptors (AMPARs) trafficking and insertion into spines following cLTP
Consistent with prior results, application of the NMDAR co-agonist glycine in the presence of a GABA receptor antagonist bicuculline led to a significant increase in the surface expression of endogenous GluA1-containing AMPARs compared to unstimulated control cells (Fig. 1a)
Summary
Brain inflammation including increases in inflammatory cytokines such as IL-1β is widely believed to contribute to the pathophysiology of Alzheimer’s disease. IL-1β-induced impairments in long-term potentiation (LTP) in acute hippocampal slices and memory functions in vivo have been well documented, the neuron-specific molecular mechanisms of IL-1β-mediated impairments of LTP and memory remain unclear. Brain inflammation is widely believed to underlie the pathophysiology of Alzheimer’s disease (AD) [1,2,3,4]. The pro-inflammatory cytokine IL-1β plays a pivotal role in brain inflammation and mediates the effect of inflammation on cognition and synaptic plasticity. IL-1β overexpression in an inducible transgenic mouse shows impaired hippocampal-dependent longterm contextual and spatial memory with normal nonhippocampal memory [6]. Several reports have demonstrated that IL-1β suppresses longterm potentiation (LTP) [9,10,11], a form of synaptic plasticity broadly defined as an activity-dependent increase in synaptic strength and considered to be a cellular
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