Redistribution of GABAB(1)Protein and Atypical GABABResponses in GABAB(2)-Deficient Mice

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