Abstracts

GABAergic circuits control the level of excitation in the hippocampus, and their disruption can induce epileptic activity. GABA[sub]A[/sub] receptors mediating tonic inhibition are assembled from different subunits than receptors responsible for phasic inhibition. The [alpha]5 subunit is thought to mediate tonic inhibition in the CA1 and CA3 areas of mice. Here, we report a significant reduction in the inhibitory tonic current of CA1 and CA3 pyramidal neurons leading to epileptiform hyperexcitability in hippocampal slices of mice lacking the [alpha]5 subunit. Horizontal and coronal brain slices (350 [mu]m thick) were prepared from C57BL/6, [alpha]5 wild-type littermates (wt) and [alpha]5 KO male mice ([sim]2 months old). Slices were continually perfused ([sim]2.0 ml/min) with bubbled aCSF with 3 mM kynurenic acid and 5 [mu]M GABA at 33-35[deg]C. Whole cell recordings were obtained from visually identified CA1 - CA3 pyramidal neurons. Tonic current was measured by calculating the net mean holding baseline current before and after application of bicuculline methiodide (BMI [gt]100 [mu]M final concentration). In contrast to a previous report (Caraiscos, et al., PNAS 2004; 101:3662), CA1 and CA3 pyramidal neurons from [alpha]5 KO mice did not show a complete loss of tonic inhibition. A residual tonic current (50% of that found in wt) was present in hippocampal pyramidal cells. The tonic current in the KO, but not in the wt, was sensitive to THDOC, a neurosteroid known to increase GABA[sub]A[/sub] conductance only when the [delta] subunits are present. Although phasic inhibition was similar between [alpha]5 KO and wt animals, there was an increased epileptiform excitability in field recordings from [alpha]5 KO. Our results demonstrate that mice lacking [alpha]5 subunits show a residual tonic current in CA1 and CA3 pyramidal neurons that is in part due to the upregulation of [delta] subunits. This compensatory change can only restore the tonic inhibition to half of its original value resulting in the hyperexcitability of pyramidal neurons. Thus tonic inhibition is an important factor in maintaining the hippocampal excitatory-inhibitory balance. (Supported by NS02808 to I.M.)