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

Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms; however, crosstalk between the CNS and peripheral immune system remains unexplored. Using parabiosis and plasma infusion, we found that blood-borne factors drive synaptic deficits in DS. Proteomic analysis revealed elevation of β2-microglobulin (B2M), a major histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemic administration of B2M in wild-type mice led to synaptic and memory defects similar to those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairments in DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR) function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactions using competitive peptides restores NMDAR-dependent synaptic function. Our findings identify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological role for circulating B2M in NMDAR dysfunction in DS and related cognitive disorders. [Display omitted] • Elevation of plasma B2M levels impairs cognitive and synaptic function • Peripheral depletion of B2M ameliorates synaptic deficits in DS mice • B2M antagonizes NMDAR function in an MHC-I- and TCR-independent manner • Blocking the B2M-NMDAR interaction corrects synaptic deficits in DS and aged mice β2-microglobulin dissociates from MHC-I complex, crosses the blood-brain barrier, antagonizes NMDA receptors, and impairs synaptic function under pathological conditions such as Down syndrome and aging. [ABSTRACT FROM AUTHOR]