Differential Compartmentalization and Distinct Functions of GABA_B Receptor Variants

GABA_B receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA). Molecular diversity in the GABA_B system arises from the GABA_B1a and GABA_B1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats that is unique to GABA_B1a. Using a combined genetic, physiological, and morphological approach, we now demonstrate that GABA_B1 isoforms localize to distinct synaptic sites and convey separate functions in vivo. At hippocampal CA3-to-CA1 synapses, GABA_B1a assembles heteroreceptors inhibiting glutamate release, while predominantly GABA_B1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABA_B1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABA_B1a in distal axons, suggesting that the sushi repeats, a conserved protein interaction motif, specify heteroreceptor localization. The constitutive absence of GABA_B1a but not GABA_B1b results in impaired synaptic plasticity and hippocampus-dependent memory, emphasizing molecular differences in synaptic GABA_B functions.