Abstracts

RATIONALE:_Administration of cholesterol synthesis inhibitors in baby rats produces a model of Neimann-Pick disease, Type C (NPC), with associated spike-wave seizures. We utilized the dissociated thalamic neuron preparation to investigate physiological mechanisms of seizures in this model. As previously reported (Wu and Fisher, Soc. for Neurosci. Abst, 2000), nucleus reticularis thalamus (nRt) neurons showed normal sensitivity to directly applied GABA, AMPA and KA. In this study, we investigated sensitivity to GABA modulators, including diazepam and the neurosteroid, pregnenolone (PGN), which is derived from cholesterol. METHODS:_Experiments were performed on Long-Evans Hooded rats, ages 14-20 days, previously given the cholesterol synthesis inhibitor U18666A (10 mg/kg i.p.) on postnatal day 1, 5, 9, 13. The nRt region was dissected, cells dissociated by enzyme, and transferred to a chamber for patch clamp recording. RESULTS:_In control rat, response to GABA 3 mM, was potentiated by diazepam 0.1 mM,1 mM and 10 mM. This potentiation by diazepam was absent in nRT cells from the NPC model. PGN potentiated effects of 3 mM GABA in nRt cells from 6 control animals, with GABA-induced currents increased as a percent of control to: 161 6 at 0.01 mM, 440 100 at 0.1 mM, and 470 79 at 1 mM. In 10 nRT cells from NPC rats, GABA-induced currents were increased a smaller amount in relation to control (% control): 100 4 at 0.01 mM, 235 22 mM at 0.1, and 319 32 at 1 mM (p < 0.01 by ANOVA). CONCLUSIONS:_nRt neurons from NPC rats show decreased GABA modulation by diazepam and by pregnenalone. Since nRt paces spike-waves in part by GABAergic mechanisms, this altered modulation may play a role in generation of spike-wave seizures. Supported by the Sandra Solheim Aiken and Marjorie Newsome Fund for Epilepsy, and the Barrow Neurological Institute Women's Board.