title: Persistent activation of microglia and NADPH oxidase [corrected] drive hippocampal dysfunction in experimental multiple sclerosis.
abstract: Cognitive impairment is common in multiple sclerosis (MS). Unfortunately, the synaptic and molecular mechanisms underlying MS-associated cognitive dysfunction are largely unknown. We explored the presence and the underlying mechanism of cognitive and synaptic hippocampal dysfunction during the remission phase of experimental MS. Experiments were performed in a chronic-relapsing experimental autoimmune encephalomyelitis (EAE) model of MS, after the resolution of motor deficits. Immunohistochemistry and patch-clamp recordings were performed in the CA1 hippocampal area. The hole-board was utilized as cognitive/behavioural test. In the remission phase of experimental MS, hippocampal microglial cells showed signs of activation, CA1 hippocampal synapses presented an impaired long-term potentiation (LTP) and an alteration of spatial tests became evident. The activation of hippocampal microglia mediated synaptic and cognitive/behavioural alterations during EAE. Specifically, LTP blockade was found to be caused by the reactive oxygen species (ROS)-producing enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We suggest that in the remission phase of experimental MS microglia remains activated, causing synaptic dysfunctions mediated by NADPH oxidase. Inhibition of microglial activation and NADPH oxidase may represent a promising strategy to prevent neuroplasticity impairment associated with active neuro-inflammation, with the aim to improve cognition and counteract MS disease progression.
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Filippo
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: de Iure
authors.affiliation: IRCCS, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Giampà
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Chiasserini
authors.affiliation: IRCCS, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy.|Sezione di Fisiologia e Biochimica, Dipartimento di Medicina Sperimentale, Università degli Studi di Perugia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.affiliation: Sezione di Fisiologia e Biochimica, Dipartimento di Medicina Sperimentale, Università degli Studi di Perugia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Orvietani
authors.affiliation: IRCCS, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Durante
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Ana
authors.initials: A
authors.lastname: Quiroga-Varela
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mancini
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Costa
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Sarchielli
authors.affiliation: IRCCS, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Fusco
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina, Università degli Studi di Perugia, Ospedale Santa Maria della Misericordia, S. Andrea delle Fratte, 06132 Perugia, Italy.|IRCCS, Fondazione Santa Lucia, via del Fosso di Fiorano 64, 00143, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D056547:CA1 Region, Hippocampal / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D003071:Cognition; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation; D005260:Female; D017774:Long-Term Potentiation; D051379:Mice; D017628:Microglia / Q000201:enzymology / Q000473:pathology; D009103:Multiple Sclerosis / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D019255:NADPH Oxidases / Q000378:metabolism*
chemical_list: D019255:NADPH Oxidases