Abstract Details

Title Activated Microglia and Neuronal Excitotoxicity in EAE Gray Matter

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 170

Objective

Background BACKGROUND: Gray matter injury correlates with progressive disability in patients with multiple sclerosis (MS). Neuronal injury and synapse loss occur in the setting of activated microglia in MS and EAE gray matter. We hypothesized that activated microglia injure neurons by increasing their vulnerability to glutamate excitotoxicity.

Design/Methods DESIGN/METHODS: We induced EAE in C57/BL6 mice by direct immunization with MOG35-55 and immunostained their brains at 3-5 weeks for monocytes/microglia (Iba1) and synaptic terminals (synapsin1). To study microglia-neuron interactions, we separately cultured primary rat hippocampal neurons and a immortalized murine microglia BV2 cells. BV2 cells stimulated with LPS or control were added to hippocampal cultures. Neuronal injury was assessed by development of dendritic beading in GFP-expressing cells imaged before and after synaptic activity triggered by KCl (90 mM 3x1 s).

Results RESULTS: In the hippocampus of EAE mice, regions of microglial activation were associated with a 25% decrease in synaptic puncta. In vitro, hippocampal neurons co-cultured with LPS-activated BV2 cells developed dendritic injury following a depolarizing KCl stimulus that caused no injury to neurons co-cultured with unstimulated BV2 cells. This injury was blocked by NMDA receptor antagonist AP-5, and was reduced by 80% in cells treated with WEB2086, a platelet-activating factor (PAF) receptor antagonist.

Conclusions CONCLUSIONS: Microglial activation is closely associated with injury to synapses in gray matter in experimental autoimmune encephalomyelitis. Microglial activation can mediate neuronal injury by increasing their vulnerability to glutamate excitotoxicity following synaptic activation that is not normally toxic, and this is mediated via receptors for the lipid-derived inflammatory molecule platelet-activating factor. This suggests potential therapeutic targets for gray matter synaptic protection in EAE and MS.

Authors/Disclosures
Matthew Bellizzi, MD (University of Rochester) PRESENTER	Dr. Bellizzi has nothing to disclose.
Harris A. Gelbard, MD, PhD (Univ of Rochester Medical Ctr)	No disclosure on file
Marius Ringelstein	Marius Ringelstein has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Marius Ringelstein has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion.

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