Persistent activation of microglia and NADPH drive hippocampal dysfunction in experimental multiple sclerosis

Massimiliano Di Filippo, Antonio De Iure, Carmela Giampà, Davide Chiasserini, Alessandro Tozzi, Pier Luigi Orvietani, Veronica Ghiglieri, Michela Tantucci, Valentina Durante, Ana Quiroga-Varela, Andrea Mancini, Cinzia Costa, Paola Sarchielli, Francesca Romana Fusco, Paolo Calabresi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number20926
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Feb 18 2016

ASJC Scopus subject areas

  • General

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