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Behavior and Physiology of Mice Lacking the GABA A ‐Receptor δ Subunit
Author(s) -
Spigelman Igor,
Li Zhiwei,
Banerjee Pradeep K.,
Mihalek Robert M.,
Homanics Gregg E.,
Olsen Richard W.
Publication year - 2002
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1046/j.1528-1157.43.s.5.8.x
Subject(s) - protein subunit , neuroscience , gabaa receptor , receptor , biology , endocrinology , psychology , medicine , chemistry , physiology , genetics , gene
Summary: Purpose: Mice with a targeted disruption of the γ‐aminobutyric acid (A) receptor (GABA A R) δ 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 δ 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 τ in −/− mutants (25 ± 3.5 ms) compared with +/+ controls (51 ± 5.2 ms). In whole‐cell patch recordings, the decay τ 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 μ M ), 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 δ mutants, but suggests predominant extrasynaptic δ subunit location in the dentate gyrus of normal mice. Faster‐decaying IPSPs likely contribute to the proepileptic phenotype of the δ mutants. Reduced neurosteroid sensitivity might also contribute to seizure susceptibility. It remains to be determined whether δ 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 δ−/− mice.