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.
Highlights
Experimental autoimmune encephalomyelitis (EAE), abnormalities in synaptic long-term potentiation (LTP) have been described in the hippocampus[4,5], a key structure for physiological cognitive functioning that seems to be vulnerable during the course of multiple sclerosis[6]
We have investigated whether the activation of microglial cells persists in the remission phase of the disease, after the resolution of motor deficits (Fig. 1)
The results obtained in the present study demonstrate that in the remission phase of experimental multiple sclerosis, CA1 hippocampal synapses fail to fully express long-term plasticity and that this synaptic dysfunction occurs in association with an impairment of cognitive performances
Summary
Experimental autoimmune encephalomyelitis (EAE), abnormalities in synaptic long-term potentiation (LTP) have been described in the hippocampus[4,5], a key structure for physiological cognitive functioning that seems to be vulnerable during the course of multiple sclerosis[6]. The aim of the present study was to investigate the presence, and the underlying mechanisms, of hippocampal dysfunction during the remission phase of experimental multiple sclerosis, after the resolution of quantifiable motor deficits. For this reason, we utilized an experimental model of multiple sclerosis that predictably follows a clinical course reminiscent of a relapsing–remitting disease, in which remissions occur spontaneously. In the remission phase of experimental autoimmune encephalomyelitis (EAE), we investigated hippocampal plasticity and behaviour and the possible mechanisms underlying their specific alteration
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