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

GABA sub(A) receptors mediate fast phasic inhibitory postsynaptic potentials and participate in slower tonic extrasynaptic inhibition. Thy1 alpha 6 mice with ectopic forebrain expression of GABA sub(A) receptor alpha 6 subunits exhibit increased extrasynaptic GABA sub(A) receptor-mediated background conductance and reduced synaptic GABA sub(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 alpha 6 subunit. In addition, receptor autoradiography of the CA1 region of Thy1 alpha 6 brain sections revealed pharmacological features that are unique for alpha 6 beta gamma 2 and alpha 6 beta receptors. The existence of atypical alpha 6 beta receptors was confirmed after completely eliminating GABA sub(A) receptors containing gamma 1, gamma 2, gamma 3 or delta subunits using serial immunoaffinity chromatography on subunit-specific GABA sub(A) receptor antibodies. Behaviourally, the Thy1 alpha 6 mice showed normal features with slightly enhanced startle reflex and struggle-escape behaviours. However, they were more sensitive to GABA sub(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 Thy1 alpha 6 mice, but not in control mice; however, the overall effect of higher tiagabine doses on the convulsion latency remained smaller in the Thy1 alpha 6 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 sub(A) antagonists.