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Reduced Inhibition and Sensitivity to Neurosteroids in Hippocampus of Mice Lacking the GABA_A Receptor Subunit

¹ Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095 ² Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, California 90095 ³ Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260

Submitted 13 November 2002; accepted in final form 8 April 2003

The subunit of the -aminobutyric acid (A) receptor (GABA_AR) is expressed postnatally mostly in the cerebellum, thalamus, and dentate gyrus. Previous studies in mice with a targeted disruption of the subunit revealed a considerable attenuation of behavioral responses to neuroactive steroids but not to other neuromodulatory drugs. Here we show that subunit loss leads to a concomitant reduction in hippocampal 4 subunit levels. These changes were accompanied by faster decay of evoked inhibitory postsynaptic potentials (IPSPs) in dentate granule neurons of –/– mutants (decay = 25 ms) compared with +/+ controls ( = 50 ms). Furthermore, the GABA_AR-mediated miniature inhibitory postsynaptic currents (mIPSCs) also decayed faster in -mutants ( = 6.3 ms) than controls ( = 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 -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 -mutant brain homogenates, indicating that the decreased alphaxalone effects on mIPSCs were due to changes in the GABA_AR protein. Faster decay of evoked IPSPs and mIPSCs in -mutants suggests presence of the subunit at both synaptic and extrasynaptic GABA_ARs. Decreased synaptic and extrasynaptic inhibition likely contributes to the pro-epileptic phenotype of -mutants. Reduced neurosteroid sensitivity might also contribute to seizure susceptibility. While the simplest explanation is that subunit-containing GABA_ARs represent the actual target of neurosteroids, it is possible that the behavioral and physiological sensitivity to neuroactive steroids is indirectly altered in the –/– mice.

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