title: Transient receptor potential vanilloid 1 channels modulate the synaptic effects of TNF-α and of IL-1β in experimental autoimmune encephalomyelitis.
abstract: 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 α (TNF-α) on glutamate-mediated excitatory postsynaptic currents, and prevented the action of interleukin 1β (IL-1β) on GABAergic inhibitory postsynaptic currents. Together, our results suggest that TRPV1 channels contrast TNF-α-mediated synaptic deficits in the peak phase of EAE and, in the chronic stages, enhance IL-1β-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.
authors.affiliation: Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, 00133 Rome, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Musumeci
authors.forename: Giorgio
authors.initials: G
authors.lastname: Grasselli
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Valentina
authors.initials: V
authors.lastname: De Chiara
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musella
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Nabila
authors.initials: N
authors.lastname: Haji
authors.forename: Helena
authors.initials: H
authors.lastname: Sepman
authors.forename: Diego
authors.initials: D
authors.lastname: Fresegna
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Georgia
authors.initials: G
authors.lastname: Mandolesi
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009924:Organ Culture Techniques; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D050916:TRPV Cation Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014409:Tumor Necrosis Factor-alpha