PURPOSE: Mice with a targeted disruption of the gamma-aminobutyric acid (A) receptor (GABA(A)R) delta subunit exhibited spontaneous seizures and a strikingly selective attenuation of responses to neuroactive steroids, but not to other neuromodulators. This study further characterized the behavior and physiology of the delta mutants. METHODS: Seizure susceptibility to pentylenetetrazol (PTZ) injection, intracellular recordings, and whole-cell patch recordings in dentate granule neurons was determined. RESULTS: Susceptibility to PTZ-induced convulsive seizures was significantly higher in -/- versus +/+ mice. In intracellular recordings, the evoked inhibitory postsynaptic potentials (IPSPs) had much faster decay tau in -/- mutants (25 +/- 3.5 ms) compared with +/+ controls (51 +/- 5.2 ms). In whole-cell patch recordings, the decay tau of pharmacologically isolated miniature spontaneous GABA(A)R-mediated synaptic currents (mIPSCs) from -/- mice was only slightly, but significantly faster (5.7 +/- 0.13 ms; n = 18) than that of +/+ controls (6.8 +/- 0.32 ms; n = 20). Furthermore, mIPSC prolongation by bath application of alphaxalone (10 microM), was much smaller in -/- mice (52 +/- 12%; n = 3) compared with +/+ littermates (192 +/- 14%; n = 3). CONCLUSIONS: Faster decay of evoked IPSPs and mIPSCs is consistent with altered GABA(A)R subunit composition in the delta mutants, but suggests predominant extrasynaptic delta subunit location in the dentate gyrus of normal mice. Faster-decaying IPSPs likely contribute to the proepileptic phenotype of the delta mutants. Reduced neurosteroid sensitivity might also contribute to seizure susceptibility. It remains to be determined whether delta subunit-containing GABA(A)Rs represent the actual target of neurosteroids or whether the behavioral and physiologic sensitivity to neurosteroids is indirectly altered in the delta-/- mice.
PURPOSE:Mice with a targeted disruption of the gamma-aminobutyric acid (A) receptor (GABA(A)R) delta subunit exhibited spontaneous seizures and a strikingly selective attenuation of responses to neuroactive steroids, but not to other neuromodulators. This study further characterized the behavior and physiology of the delta mutants. METHODS:Seizure susceptibility to pentylenetetrazol (PTZ) injection, intracellular recordings, and whole-cell patch recordings in dentate granule neurons was determined. RESULTS: Susceptibility to PTZ-induced convulsive seizures was significantly higher in -/- versus +/+ mice. In intracellular recordings, the evoked inhibitory postsynaptic potentials (IPSPs) had much faster decay tau in -/- mutants (25 +/- 3.5 ms) compared with +/+ controls (51 +/- 5.2 ms). In whole-cell patch recordings, the decay tau of pharmacologically isolated miniature spontaneous GABA(A)R-mediated synaptic currents (mIPSCs) from -/- mice was only slightly, but significantly faster (5.7 +/- 0.13 ms; n = 18) than that of +/+ controls (6.8 +/- 0.32 ms; n = 20). Furthermore, mIPSC prolongation by bath application of alphaxalone (10 microM), was much smaller in -/- mice (52 +/- 12%; n = 3) compared with +/+ littermates (192 +/- 14%; n = 3). CONCLUSIONS: Faster decay of evoked IPSPs and mIPSCs is consistent with altered GABA(A)R subunit composition in the delta mutants, but suggests predominant extrasynaptic delta subunit location in the dentate gyrus of normal mice. Faster-decaying IPSPs likely contribute to the proepileptic phenotype of the delta mutants. Reduced neurosteroid sensitivity might also contribute to seizure susceptibility. It remains to be determined whether delta subunit-containing GABA(A)Rs represent the actual target of neurosteroids or whether the behavioral and physiologic sensitivity to neurosteroids is indirectly altered in the delta-/- mice.
Authors: Ryan W Lewis; John Mabry; Jason G Polisar; Kyle P Eagen; Bruce Ganem; George P Hess Journal: Biochemistry Date: 2010-06-15 Impact factor: 3.162
Authors: Dev Chandra; David F Werner; Jing Liang; Asha Suryanarayanan; Neil L Harrison; Igor Spigelman; Richard W Olsen; Gregg E Homanics Journal: Alcohol Clin Exp Res Date: 2007-12-12 Impact factor: 3.455