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This Article Full Text Full Text (PDF) All Versions of this Article: 99/3/1285    most recent 01180.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Feng, H.-J. Articles by Macdonald, R. L. PubMed PubMed Citation Articles by Feng, H.-J. Articles by Macdonald, R. L.

Alterations of GABA_A-Receptor Function and Allosteric Modulation During Development of Status Epilepticus

¹Departments of Neurology, ²Molecular Physiology and Biophysics, ³Pharmacology, and ⁴Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee

Submitted 23 October 2007; accepted in final form 19 January 2008

Partial limbic seizures in rodents induced by pilocarpine progress from stages I–II (mouth and facial movements; head nodding) to stage III (forelimb clonus) and then progress rapidly to stages IV–V (generalized limbic seizures; rearing, and rearing with falling) followed by status epilepticus (SE). Although limbic seizures in rodents are terminated by benzodiazepines, a group of -aminobutyric acid type A (GABA_A)–receptor positive modulators, significant pharmacoresistance to benzodiazepines develops within minutes during SE. The alterations of GABA_A-receptor function and allosteric modulation during development of SE are poorly understood. We induced seizures in juvenile rats by administration of lithium followed by pilocarpine, and whole cell recordings of miniature inhibitory postsynaptic currents (mIPSCs) were obtained from hippocampal dentate granule cells in brain slices. Compared with a sham-treated group, mIPSC amplitude was reduced and decay was accelerated at onset of the first occurrence of stage III (S3) seizures [S3(0)], resulting in a reduction in the total charge transfer at S3(0). Recovery of mIPSC amplitude and prolongation of mIPSC decay occurred 30 min after onset of S3 seizures [S3(30)]. The mIPSC frequency was not altered for S3(0) and S3(30) neurons compared with sham neurons. The net enhancement of total charge transfer by diazepam was smaller for S3(30) than that for sham and S3(0) neurons; however, the net reduction of total charge transfer by zinc was greater for S3(30) than that for sham and S3(0) neurons. These findings suggest that substantial plastic changes of GABA_A-receptor function and allosteric modulation occur rapidly in neurons from juvenile animals during development of SE.