Dual role of GABAB receptor in oligodendrocyte function and immune modulation in experimental multiple sclerosis

Abstract

GABAB receptors (GABABR) mediate the actions of the inhibitory neurotransmitter GABA in the central nervous system, regulating key processes such as synaptic activity, interneuron communication and excitation-inhibition balance in the brain. Recent studies using the GABABR agonist baclofen have revealed a critical role for these receptors in promoting oligodendroglial differentiation in both health and disease, highlighting their potential as therapeutic targets in demyelinating diseases such as multiple sclerosis (MS). In this study, we identify a dual role for oligodendroglial GABABR in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Conditional deletion of the GABAB1 subunit in NG2+ cells ameliorates acute disease symptoms while inducing an immune-like phenotype in oligodendrocytes. This immunomodulatory role is further supported by pharmacological activation of GABABR in oligodendrocytes, which reduces the expression of MHC class II in these cells. Notably, baclofen treatment after EAE symptom onset attenuates the course of the disease while enhancing oligodendrocyte progenitor cell differentiation and suppressing T cell infiltration into demyelinating lesions. Moreover, prophylactic baclofen administration delays disease onset and further decreases immune cell recruitment into the spinal cord, underscoring its potent immunomodulatory effect. These data demonstrate that GABABR signaling exerts context-dependent effects on both oligodendrocyte lineage progression and neuroinflammatory responses. Importantly, these compelling findings validate baclofen, a drug already approved for MS-associated spasticity, as a promising candidate for therapies targeting both inflammation and remyelination, advancing our understanding of glial-immune interactions in demyelinating diseases and supporting the translational potential of GABABR modulation in MS.