GABA _B receptor-mediated modulation of metabotropic glutamate signaling and synaptic plasticity in central neurons

In mammalian brains, γ-amino butyric acid (GABA) is the most ubiquitous inhibitory neurotransmitter and neuromodulator. The G _i/o protein-coupled GABA receptor termed B-type GABA receptor (GABA _B R) has been recognized as one of the major mediators of the inhibitory effects of GABA. Several years ago, Hirono et al. and our group independently found that GABA _B R mediates non-inhibitory effects in cerebellar Purkinje cells. In this cell type, GABA _B R co-localizes with type-1 metabotropic glutamate receptor (mGluR1), a G _q/11 protein-coupled receptor around the postsynaptic membrane of the excitatory synapses. At that site, GABA _B R is not exposed to the direct bombardment of GABA released from the terminals of inhibitory neurons. Instead, the receptor may sense a low concentration of GABA and Ca ²⁺ usually contained in the extracellular fluid and a relatively high concentration of GABA spilt over from the neighboring active inhibitory synapses. In response to these ambient ligands, GABA _B R increases the ligand affinity of mGluR1 independently of G _i/o protein and augments mGluR1-coupled intracellular signaling via G _i/o protein. These GABA _B R-mediated modulations may facilitate mGluR1-mediated neuronal responses including cerebellar long-term depression, a form of synaptic plasticity crucial for cerebellar motor learning. In this article, we present current knowledge on a new role of GABA _B R as an ambience-dependent regulator of synaptic signaling.