Abnormal benzodiazepine and zinc modulation of GABAA receptors in an acquired absence epilepsy model.
Brain cholesterol synthesis inhibition (CSI) at a young age in rats has been shown to be a faithful model of acquired absence epilepsy, a devastating condition for which few therapies or models exist. We employed the CSI model to study cellular mechanisms of acquired absence epilepsy in Long-Evans Hooded rats. Patch-clamp, whole-cell recordings were compared from neurons acutely dissociated from the nucleus reticularis of thalamus (nRt) treated and untreated with a cholesterol synthesis inhibitor, U18666A. In U18666A-treated animals, 91% of rats developed EEG spike-waves (SWs). Patchclamp results revealed that although there was no remarkable change in GABAA receptor affinity, both a loss of ability of benzodiazepines to enhance GABAA-receptor responses and an increase of Zn2+ inhibition of GABAA-receptor responses of nRt neurons occurred in Long-Evans Hooded rats previously administered U18666A. This change was specific, since no significant changes were found in neurons exposed to the GABA allosteric modulator, pentobarbital. Taken collectively, these findings provide evidence for abnormalities in benzodiazepine and Zn2+ modulation of GABAA receptors in the CSI model, and suggest that decreased gamma2 subunit expression may underlie important aspects of generation of thalamocortical SWs in atypical absence seizures. The present results are also consistent with recent findings that mutation of the gamma2 subunit of the GABAA receptor changes benzodiazepine modulation in families with generalized epilepsy syndromes.
Medical Subject Headings
Androstenes; Animals; Anticonvulsants; Benzodiazepines; Diazepam; Disease Models, Animal; Enzyme Inhibitors; Epilepsy, Absence; GABA Modulators; Membrane Potentials; Patch-Clamp Techniques; Pentobarbital; Rats; Rats, Long-Evans; Receptors, GABA-A; Thalamic Nuclei; Zinc; gamma-Aminobutyric Acid
Digital Object Identifier (DOI)
Wu, Jie; Ellsworth, Kevin; Ellsworth, Marc; Schroeder, Katherine M; Smith, Kris A; and Fisher, Robert S, "Abnormal benzodiazepine and zinc modulation of GABAA receptors in an acquired absence epilepsy model." (2004). Neurosurgery. 794.