Abstract
IntroductionTumor necrosis factor alpha (TNFα) plays a physiological role in controlling synaptic transmission and plasticity in the healthy central nervous system by modulating glutamate receptor trafficking to the plasma membrane. TNFα expression is also rapidly induced in response to tissue injury and infection. By promoting the insertion of Ca2+ permeable-AMPA receptors into the neuronal plasma membrane, this cytokine may cause excessive Ca2+ influx into neurons, thus enhancing neuronal death.MethodsPrimary cultures of cortical neurons were obtained from E18 foetal mice and incubated for 24 h with adult neural stem cells (aNPCs) either stimulated with lipopolysaccharide (LPS+aNPCs) or not (aNPCs). Cultures were treated with TNFα (100 ng/ml), and electrophysiological recordings were performed in different conditions to evaluate the effect of the cytokine on neuronal transmission.ResultsIn this study, we demonstrate that aNPCs from the subventricular zone reverse the effects induced by the cytokine. Moreover, we show that the effect of aNPCs on cortical neurons is mediated by cannabinoid CB1 receptor activation.ConclusionThese data suggest that the role of aNPCs in preventing excitatory neurotransmission potentiation induced by TNFα on cortical neurons may have important implications for pathologies characterized by an inflammatory component affecting cortical neurons such as Alzheimer’s disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0158-2) contains supplementary material, which is available to authorized users.
Highlights
Tumor necrosis factor alpha (TNFα) plays a physiological role in controlling synaptic transmission and plasticity in the healthy central nervous system by modulating glutamate receptor trafficking to the plasma membrane
TNFα increases amplitude and frequency of miniature currents in primary cortical neurons several studies have shown that TNFα increases synaptic strength at hippocampal excitatory synapses by rapidly inserting AMPA receptors via TNFR1 receptor activation [30], little has been reported in different neuronal cell types [31, 32]
To address whether this effect is restricted to hippocampal neurons or occurs at cortical synapses, we grew cultures of primary neurons derived from the cerebral cortex and exposed them to TNFα (100 ng/ml) for 30 min before recording miniature excitatory postsynaptic current (mEPSC)
Summary
Tumor necrosis factor alpha (TNFα) plays a physiological role in controlling synaptic transmission and plasticity in the healthy central nervous system by modulating glutamate receptor trafficking to the plasma membrane. The pro-inflammatory cytokine tumor necrosis factor alpha (TNFα), released by glial cells, is involved in several brain functions. The cytokine is thought to be responsible for the activitydependent homeostatic regulation of synaptic connectivity, which consists of the increase of synaptic strength in response to prolonged blockade of activity. This process, termed synaptic scaling, involves the insertion of AMPA receptors, mobilized from intracellular stores, into the plasma membrane [1,2,3,4]. A continuous crosstalk between immune cells and NPCs appears to determine both the efficacy of endogenous regenerative responses and mechanism of action as well as the fate and functional integration of grafted NPCs, through different kinds of receptors located on their membranes [20, 21]
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