Redistribution of GABA_B(1) protein and atypical GABA_B responses in GABA_B(2)-deficient mice

GABA_B receptors mediate slow synaptic inhibition in the nervous system. In transfected cells, functional GABA_B receptors are usually only observed after coexpression of GABA_B(1) and GABA_B(2) subunits, which established the concept of heteromerization for G-protein-coupled receptors. In the heteromeric receptor, GABA_B(1) is responsible for binding of GABA, whereas GABA_B(2) is necessary for surface trafficking and G-protein coupling. Consistent with these in vitro observations, the GABA_B(1) subunit is also essential for all GABA_B signaling in vivo. Mice lacking the GABA_B(1) subunit do not exhibit detectable electrophysiological, biochemical, or behavioral responses to GABA_B agonists. However, GABA_B(1) exhibits a broader cellular expression pattern than GABA_B(2), suggesting that GABA_B(1) could be functional in the absence of GABA_B(2). We now generated GABA_B(2)-deficient mice to analyze whether GABA _B(1) has the potential to signal without GABA_B(2) in neurons. We show that GABA_B(2)^-/- mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABA_B(1)^-/- mice. This clearly demonstrates that the lack of heteromeric GABA_B(1,2) receptors underlies these phenotypes. To our surprise and in contrast to GABA _B(1)^-/- mice, we still detect atypical electrophysiological GABA_B responses in hippocampal slices of GABA_B(2)^-/- mice. Furthermore, in the absence of GABA _B(2), the GABA_B(1) protein relocates from distal neuronal sites to the soma and proximal dendrites. Our data suggest that association of GABA_B(2) with GABA_B(1) is essential for receptor localization in distal processes but is not absolutely necessary for signaling. It is therefore possible that functional GABA_B receptors exist in neurons that naturally lack GABA_B(2) subunits.