Persistent activation of microglia and NADPH oxidase [corrected] drive hippocampal dysfunction in experimental...

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Cognitive impairment is a prevalent symptom in multiple sclerosis (MS).
• The precise synaptic and molecular mechanisms driving cognitive dysfunction in MS remain largely unelucidated.
• Understanding these mechanisms during remission is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate cognitive and synaptic hippocampal dysfunction during the remission phase of experimental autoimmune encephalomyelitis (EAE), a model for MS.
• To identify the underlying molecular mechanisms, particularly the role of microglial activation.
• To explore potential therapeutic targets for mitigating MS-associated cognitive deficits.

Main Methods:

• Utilized a chronic-relapsing EAE model in mice, focusing on the remission phase after motor symptom resolution.
• Employed immunohistochemistry and patch-clamp electrophysiology in the CA1 hippocampal region.
• Assessed cognitive function using the hole-board test.

Main Results:

• Activated hippocampal microglia were observed during the remission phase of EAE.
• Impaired long-term potentiation (LTP) at CA1 hippocampal synapses and deficits in spatial memory tests were evident.
• Microglial activation mediated synaptic and cognitive alterations, with NADPH oxidase identified as the enzyme responsible for LTP blockade via reactive oxygen species (ROS).

Conclusions:

• Microglial activation persists into the remission phase of experimental MS, leading to synaptic dysfunction.
• The enzyme NADPH oxidase plays a key role in mediating these synaptic deficits through ROS production.
• Inhibiting microglial activation and NADPH oxidase presents a potential therapeutic strategy to preserve neuroplasticity and improve cognition in MS.