Differential compartmentalization and distinct functions of GABAB receptor variants

GABA(B) receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, gamma-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.