Persistent activation of microglia and NADPH oxidase 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.

Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

“…Other research groups confirmed this evidence, suggesting a key role for this cytokine in synaptic plasticity defects observed during neuroinflammatory processes [58,66,[68][69][70]. However, endogenous IL-1β is normally expressed at low levels in control conditions, and it has been proposed to be essential for the physiological induction of hippocampal LTP and consolidation of memory [65,71].…”

“…In our laboratory, we found an impaired LTP induction in the hippocampal CA1 area both during the acute inflammatory peak phase of EAE [68] and the later remission phase [58]. As experimental model for MS, we induced EAE in Biozzi ABH mice, which are particularly prone to develop autoimmune responses, by the injection of syngeneic spinal cord homogenate [68].…”

“…Indeed, an astrocyte-derived mediator, such as lactosylceramide, could play a role in CNS inflammation and neuronal degeneration in experimental models of MS, interfering with glutamate transmission [55][56][57]. Similarly, microglia is gaining attention as a central regulator of synaptic transmission during neuroinflammation and other neurodegenerative disorders [2,3,48,58].…”

Pattern separation performance is decreased in patients with early multiple sclerosis

“…Given that dentate gyrus morphological abnormalities have been described in MS (Gold et al, 2010;, and given the particular importance of the dentate gyrus for pattern separation, our results provide additional neuropsychological support for an early dentate gyrus disruption during the course of MS. This selective vulnerability of dentate granular neurons at the early stage of MS could be related to a differential pattern of microglial activation in the dentate gyrus compared to other hippocampal subfields (Di Filippo et al, 2016;Planche et al, 2017), but the exact underlying molecular mechanisms remain unclear.…”

“…Several prior studies support that hippocampal dysfunction primarily mediates memory impairment in MS, both in the human disease (Sicotte et al, 2008;Dutta et al, 2011;Hulst et al, 2012;Planche et al, 2016) and in animal models such as experimental autoimmune encephalomyelitis (EAE) (Di Filippo et al, 2016;Nisticò et al, 2013;Planche et al, 2017). However, the precise neuropsychological and anatomical mechanisms leading to loss of episodic memory performance still remain poorly understood.…”