β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function

Area of Science:

• Neuroimmunology
• Synaptic Plasticity
• Molecular Neuroscience

Background:

• Down syndrome (DS) involves neurological and immune symptoms, with unexplored CNS-peripheral immune system interactions.
• Synaptic deficits are a hallmark of DS, impacting cognitive function.

Purpose of the Study:

• To investigate the role of blood-borne factors in DS-associated synaptic deficits.
• To identify specific molecules mediating CNS-immune crosstalk in DS.

Main Methods:

• Parabiosis and plasma infusion experiments in mouse models.
• Proteomic analysis of human DS plasma.
• Systemic administration of beta-2 microglobulin (B2M) and anti-B2M antibodies.
• Investigating B2M-NMDA receptor (NMDAR) interactions.

Main Results:

• Blood-borne factors were identified as drivers of synaptic deficits in DS.
• Elevated B2M levels in DS plasma correlated with synaptic and memory impairments.
• Genetic or antibody-mediated B2M reduction ameliorated synaptic deficits in DS mice.
• B2M was shown to antagonize NMDAR function by interacting with the GluN1-S2 loop.

Conclusions:

• Circulating B2M is an endogenous NMDAR antagonist.
• B2M plays a pathophysiological role in NMDAR dysfunction in Down syndrome.
• Targeting B2M-NMDAR interactions offers a potential therapeutic strategy for cognitive disorders in DS.