Helping Out

Science Signaling  16 Feb 2010:
Vol. 3, Issue 109, pp. ec54
DOI: 10.1126/scisignal.3109ec54

γ-aminobutyric acid (GABA) is a neurotransmitter that acts in the central nervous system (CNS) to inhibit neuronal excitability. GABA also acts in the immune system to decrease inflammatory responses; however, its role in adaptive immune responses remains poorly characterized. Noting that multiple sclerosis (MS) is an inflammatory autoimmune disease of the CNS, Bhat et al. sought to determine the effects of GABA signaling in mice with experimental autoimmune encephalomyelitis (EAE), a model of human MS. Western blotting analysis showed that dendritic cells (DCs) and macrophages contained glutamic acid decarboxylase, the enzyme that synthesizes GABA. Patch-clamp experiments demonstrated that macrophages possessed functional GABA-A receptors (GABA-A-Rs), and reverse transcription polymerase chain reaction (RT-PCR) assays showed that T cells and macrophages expressed genes that encode GABA transporter proteins and GABA transaminase (GABAT), the main enzyme that degrades GABA. In vitro experiments demonstrated that GABAergic compounds, such as an analog of GABA, an agonist of GABA-A-R, and an inhibitor of GABAT, inhibited the production of proinflammatory cytokines by DCs but not by T cells. The effects of GABAergic agents on DCs were associated with the decreased phosphorylation and activation of mitogen-activated protein kinases. When treated with GABAergic agents, mice with EAE (which was induced by immunization with a myelin peptide) had slower progression to disease and milder symptoms than did untreated EAE mice. Furthermore, naïve mice that received immune cells from mice that had been immunized with myelin peptide and treated with GABAergic compounds also exhibited less severe disease than did mice that received cells that had not been treated with GABAergic compounds. In light of these findings, the authors suggest that modulating the GABA system may provide therapeutic effects in the treatment of MS.

R. Bhat, R. Axtell, A. Mitra, M. Miranda, C. Lock, R. W. Tsien, L. Steinman, Inhibitory role for GABA in autoimmune inflammation. Proc. Natl. Acad. Sci. U.S.A. 107, 2580–2585 (2010). [Abstract] [Full Text]