Behavioural correlates of an altered balance between synaptic and extrasynaptic GABA A ergic inhibition in a mouse model

GABA A receptors mediate fast phasic inhibitory postsynaptic potentials and participate in slower tonic extrasynaptic inhibition. Thy1α6 mice with ectopic forebrain expression of GABA A receptor α6 subunits exhibit increased extrasynaptic GABA A receptor‐mediated background conductance and reduced synaptic GABA A receptor currents in hippocampal CA1 neurons [W. Wisden et al . (2002) Neuropharmacology 43, 530–549]. Here we demonstrate that isolated CA1 neurons of these mice showed furosemide‐sensitivity of GABA‐evoked currents, confirming the functional expression of α6 subunit. In addition, receptor autoradiography of the CA1 region of Thy1α6 brain sections revealed pharmacological features that are unique for α6βγ2 and α6β receptors. The existence of atypical α6β receptors was confirmed after completely eliminating GABA A receptors containing γ1, γ2, γ3 or δ subunits using serial immunoaffinity chromatography on subunit‐specific GABA A receptor antibodies. Behaviourally, the Thy1α6 mice showed normal features with slightly enhanced startle reflex and struggle‐escape behaviours. However, they were more sensitive to GABA A antagonists DMCM (shorter latency to writhing clonus) and picrotoxinin (shorter latency to generalized convulsions). Tiagabine, an antiepileptic GABA‐uptake inhibitor that increases brain GABA levels, delayed picrotoxinin‐induced convulsions at a low dose of 3.2 mg/kg in Thy1α6 mice, but not in control mice; however, the overall effect of higher tiagabine doses on the convulsion latency remained smaller in the Thy1α6 mice. Altered balance between extrasynaptic and synaptic receptors thus affects seizure sensitivity to GABAergic convulsants. Importantly, the increased extrasynaptic inhibition, even when facilitated in the presence of tiagabine, was not able fully to counteract enhanced seizure induction by GABA A antagonists.