AMPAR inhibition lowers S1P in human blood and improves murine autoimmune neuroinflammation by blocking T cell egress from lymph nodes

Glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated signaling in neurons acts through regulation of ion channels. In T cells, we uncovered a noncanonical AMPAR-mediated metabotropic G_i protein-coupled signaling pathway. Selective blockade of AMPAR ameliorated disease severity in experimental autoimmune encephalomyelitis (EAE) both in SJL mice, which typically show a relapsing-remitting disease course, and in C57BL/6 mice, representing chronic disease activity. AMPAR blockade led to a retention of T cells in lymph nodes resulting in reduced T cell numbers within the central nervous system. RNA sequencing and functional analysis of the lymphocyte AMPAR pathway revealed that the AMPAR antagonist perampanel inhibited G_i protein-coupled signaling and induced migration-modifying transcription programs, including CD69. CD69⁺ T cells showed down-regulated expression of sphingosine 1-phosphate (S1P) receptor, a key regulator of T cell egress. Reduced T cell egress from lymph nodes upon AMPAR blockade was rescued by anti-CD69 antibody treatment or addition of S1P. Perampanel treatment additionally reduced S1P blood concentrations in mice and patients with epilepsy. Combined AMPAR and S1P receptor inhibition had an additive beneficial effect on disease severity in C57BL/6 EAE, and single AMPAR treatment was sufficient to almost completely abolish disease development in SJL EAE. Our findings suggest that AMPAR blockade can counteract neuroinflammation caused by the infiltration of T cells into the central nervous system in conditions such as multiple sclerosis.