Reduced Inhibition and Sensitivity to Neurosteroids in Hippocampus of Mice Lacking the GABAAReceptor δ Subunit

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Abstract
The δ subunit of the γ-aminobutyric acid (A) receptor (GABAAR) is expressed postnatally mostly in the cerebellum, thalamus, and dentate gyrus. Previous studies in mice with a targeted disruption of the δ subunit revealed a considerable attenuation of behavioral responses to neuroactive steroids but not to other neuromodulatory drugs. Here we show that δ subunit loss leads to a concomitant reduction in hippocampal α4 subunit levels. These changes were accompanied by faster decay of evoked inhibitory postsynaptic potentials (IPSPs) in dentate granule neurons of –/– mutants (decay τ = 25 ms) compared with +/+ controls (τ = 50 ms). Furthermore, the GABAAR-mediated miniature inhibitory postsynaptic currents (mIPSCs) also decayed faster in δ-mutants (τ = 6.3 ms) than controls (τ = 7.2 ms) and had decreased frequency (controls, 10.5 Hz; mutants, 6.6 Hz). Prolongation of mIPSCs by the neuroactive steroid anesthetic, alphaxalone (1–10 μM), was smaller in δ-mutants (at 10 μM, 65% increase) compared with +/+ littermates (308% increase). In competition binding experiments, alphaxalone (0.03–1 μM) modulation of [35S]t-butylbicyclophosphorothionate binding was reduced in δ-mutant brain homogenates, indicating that the decreased alphaxalone effects on mIPSCs were due to changes in the GABAAR protein. Faster decay of evoked IPSPs and mIPSCs in δ-mutants suggests presence of the δ subunit at both synaptic and extrasynaptic GABAARs. Decreased synaptic and extrasynaptic inhibition likely contributes to the pro-epileptic phenotype of δ-mutants. Reduced neurosteroid sensitivity might also contribute to seizure susceptibility. While the simplest explanation is that δ subunit-containing GABAARs represent the actual target of neurosteroids, it is possible that the behavioral and physiological sensitivity to neuroactive steroids is indirectly altered in the δ –/– mice.