Transient receptor potential vanilloid 1 (TRPV1) channels are involved in several inflammatory diseases. However, their action is still controversial, and both pro-inflammatory and anti-inflammatory roles have been described. We used a strain of TRPV1-KO mice to characterize the role of these channels in experimental autoimmune encephalomyelitis (EAE), which models multiple sclerosis (MS) in mice. EAE mice showed higher lethality in the peak phase of the disease and a better recovery of the surviving animals in the chronic stages, compared to their wild-type (WT) counterparts. By means of whole-cell patch clamp experiments in corticostriatal brain slices, we found that the absence of TRPV1 channels exacerbated the defect of glutamate transmission occurring in the peak phase of EAE, and attenuated the alterations of GABA synapses in the chronic phase of EAE, thus paralleling the dual effects of TRPV1-KO on the motor deficits of EAE mice. Furthermore, in slices from non-EAE mice, we found that genetic or pharmacological blockade of TRPV1 channels enhanced the synaptic effects of tumor necrosis factor alpha (TNF-alpha) on glutamate-mediated excitatory postsynaptic currents, and prevented the action of interleukin 1 beta (IL-1 beta) on GABAergic inhibitory postsynaptic currents. Together, our results suggest that TRPV1 channels contrast TNF-alpha-mediated synaptic deficits in the peak phase of EAE and, in the chronic stages, enhance IL-1 beta-induced GABAergic defects. The opposing interplay with the synaptic actions of the two major pro-inflammatory cytokines might explain the bimodal effects of TRPV1 ablation on the motor deficits of EAE, and suggests that the inflammatory milieu determines whether TRPV1 channels exert preferentially aversive or protective effects on neurons during neuroinflammatory diseases.
|Titolo:||Transient receptor potential vanilloid 1 channels modulate the synaptic effects of TNF-alpha and of IL-1 beta in experimental autoimmune encephalomyelitis|
|Data di pubblicazione:||2011|
|Appare nelle tipologie:||1.1 Articolo in rivista|