title: Abnormal activity of the Na/Ca exchanger enhances glutamate transmission in experimental autoimmune encephalomyelitis.
abstract: It is increasingly accepted that excessive glutamate release plays a key role in the pathophysiology of grey matter damage in multiple sclerosis (MS). The mechanisms causing abnormal glutamate transmission in this disorder are however largely unexplored. By means of electrophysiological recordings from single striatal neurons in slices, we found that the presymptomatic and acute phases of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, are associated with enhanced synaptic release of glutamate. The reverse mode of action of axonal Na(+)/Ca(++) exchanger, secondary to abnormal functioning of voltage-dependent Na(+) channels, was identified as a major cause of this alteration. In fact, inhibition of the Na(+)/Ca(++) exchanger with bepridil or with KB-R7943, which selectively blocks the reverse mode of the exchanger, reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from striatal neurons in EAE mice but not in control animals. In the presence of tetrodotoxin (TTX), a blocker of voltage-dependent Na(+) channels, the effect of bepridil was normalized in acute (25 days post-immunization) EAE mice, indicating that axonal accumulation of Na(+) ions flowing through voltage-dependent Na(+) channels plays a role in the abnormal activity of the Na(+)/Ca(++) exchanger in EAE. Our data reveal an important role of Na(+)/Ca(++) exchanger and of voltage-dependent Na(+) channels in the pathological process of EAE, and provide a rationale for the use of neuroprotective strategies since the very early stages of MS.
authors.affiliation: Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, 00133 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Valentina
authors.initials: V
authors.lastname: De Chiara
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musella
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavasinni
authors.forename: Luca
authors.initials: L
authors.lastname: Muzio
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology; D055724:Electrophysiological Phenomena; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D011597:Psychomotor Performance / Q000502:physiology; D017661:Receptors, Presynaptic / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000779:Anesthetics, Local; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D017661:Receptors, Presynaptic; D019831:Sodium-Calcium Exchanger; D018698:Glutamic Acid; D013779:Tetrodotoxin