Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Glutamate neurotransmission is altered in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE).
• EAE is characterized by increased glutamate transmission and AMPA receptor upregulation.
• The specific role of N-methyl-D-aspartate (NMDA) receptors in EAE-induced synaptic changes remains unclear.

Purpose of the Study:

• To investigate the contribution of NMDA receptors to glutamate transmission alterations in EAE.
• To assess the impact of NMDA receptor activity on EAE disease severity.
• To explore NMDA receptor signaling as a potential therapeutic target for MS.

Main Methods:

• Neurophysiological recordings to assess synaptic transmission.
• Morphological and Western blot analyses for receptor and cellular changes.
• Metabolic assessments using NAD(P)H autofluorescence to evaluate mitochondrial function.
• Clinical scoring to monitor disease progression in EAE mice.

Main Results:

• EAE mice exhibited increased glutamate release dependent on NMDA receptor activity.
• Presynaptic NMDA receptors were found to be overactive in EAE, enhancing glutamate release via sodium channels.
• EAE induced mitochondrial dysfunction, linked to glutamate and NMDA receptor activity.
• Pharmacological blockade of NMDA receptors ameliorated synaptic deficits and clinical symptoms in EAE mice.

Conclusions:

• NMDA receptor signaling is sensitized in EAE and contributes to disease progression.
• Targeting NMDA receptors may offer a neuroprotective strategy for multiple sclerosis.
• These findings highlight the potential of NMDA receptor antagonists in MS treatment.