Epilepsy , Hyperalgesia , Impaired Memory , and Loss of Pre - and Postsynaptic GABAB Responses in Mice Lacking

1 others did not find any evidence for subtypes (Wald-pression pattern of the two cloned subunits matches University of Geneva the brain distribution of GABA B binding sites (Bischoff CH-1211 Geneva 4 et al., 1999), and the heterodimeric GABA B(1,2) receptor Switzerland was shown to activate all well-characterized GABA B ef-fector pathways in transfected cells (Marshall et al., 1999). These findings, and the fact that cloning has failed Summary to identify pharmacologically distinct receptor sub-types, led to speculations that the cloned subunits might GABA B (␥-aminobutyric acid type B) receptors are im-be responsible for most, possibly all, GABA B-mediated portant for keeping neuronal excitability under control. effects. Whether the pharmacological heterogeneity ob-Cloned GABA B receptors do not show the expected served with native receptors relates to differences in pharmacological diversity of native receptors and it is the effector systems or to the existence of additional, unknown whether they contribute to pre-as well as as yet unidentified, GABA B receptor subtypes remains postsynaptic functions. Here, we demonstrate that a key issue in the GABA B field. In that context, it is Balb/c mice lacking the GABA B(1) subunit are viable, interesting to note that the GABA B(2) mRNA is exclusively exhibit spontaneous seizures, hyperalgesia, hyperlo-expressed in neurons, while the GABA B(1) mRNA is local-comotor activity, and memory impairment. Upon ized to both neurons and glia (Clark et al., 2000). More-GABA B agonist application, null mutant mice show nei-over, while GABA B(2) mRNA is barely detectable in the ther the typical muscle relaxation, hypothermia, or rat caudate putamen, the mRNA for GABA B(1) is relatively delta EEG waves. These behavioral findings are paral-abundant in this region. In support of a differential distri-leled by a loss of all biochemical and electrophysio-bution of GABA B(1) and GABA B(2) protein, the pattern of logical GABA B responses in null mutant mice. This immunoreactivity of the two proteins diverges in the rat demonstrates that GABA B(1) is an essential component striatum (Ng and Yung, 2001). These recent findings of pre-and postsynaptic GABA B receptors and casts have further nourished speculations as to the existence doubt on the existence of proposed receptor subtypes. of additional GABA B receptor proteins (Clark et al., 2000; Couve et al., 2000). It was hypothesized that GABA B(1) Introduction and GABA B(2) constitute functional receptors independent of each other, in association with proteins that are GABA B receptors are the metabotropic receptors …