Platelet-Activating Factor Receptors Mediate Excitatory Postsynaptic Hippocampal Injury in Experimental Autoimmune...

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Gray matter degeneration contributes to progressive disability in multiple sclerosis (MS).
• This degeneration can occur independently of white matter pathology, such as demyelination and axon injury.
• Neurons may suffer direct excitatory injury within gray matter.

Purpose of the Study:

• To investigate direct neuronal injury in gray matter in a mouse model of MS.
• To determine the role of microglia and platelet-activating factor receptor (PAFR) signaling in this injury.
• To assess the therapeutic potential of PAFR blockade for protecting synapses in MS.

Main Methods:

• Used experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice with hippocampal degeneration.
• Quantified synaptic density using immunofluorescent staining for PSD95 and VGLUT1.
• Utilized in vitro microglial-neuronal co-cultures and in vivo treatment with PAFR antagonist BN52021.

Main Results:

• Observed a 28% loss of PSD95-positive excitatory postsynaptic puncta in the hippocampus (area CA1) in EAE mice.
• Found that activated microglia and PSD95-positive debris colocalized with synaptic loss.
• In vitro, activated microglia increased neuronal vulnerability to excitotoxicity via PAFR signaling.
• In vivo, BN52021 prevented synapse loss without affecting EAE development or microglial activation.

Conclusions:

• Postsynaptic structures are primary targets of gray matter injury in autoimmune neuroinflammatory disease.
• Microglial activation promotes excitotoxic injury via PAFR-mediated signaling.
• PAFR blockade offers a potential neuroprotective strategy for MS by preserving synaptic integrity.