Abstracts

Rationale: This study assessed the potential for the naked mole rat (Heterocephalus Glaber) as an animal model for epilepsy research. These subterranean rodents from eastern Africa have evolved a number of unique features that may yield clues into the mechanisms of epilepsy. First, they utilize a cooperative breeding system (like ants or termites) wherein most adult animals (95%) have negligible gonadal hormone secretion, allowing for the control of puberty onset in adults. Second, they are the longest-lived rodent species, living over 29 years in captivity, providing a useful model for the study of epilepsy and aging. Third, due to their environmental niche, they are hypoxia and hypercapnia tolerant, allowing for investigation of the relationship of O2 and CO2 to neuronal excitability independent of neuronal death. Fourth, they have poor body temperature control, allowing for new approaches to measure the relationship between seizures and brain temperature. Therefore, behavioral and electrophysiological measures were taken to provide a basic understanding of baseline epileptic activity in naked mole rats. Methods: Naked mole rats, generously donated by Bruce Goldman, were housed together by colony, with colonies ranging from 6 to 38 animals. To determine the effects of an inspiratory challenge on seizure behavior, O2 was lowered in a nearly airtight housing environment (a series of tub cages connected by polycarbonate tubing) using an oxygen sensor coupled to a valve regulating CO2 infusion. The colony (n=22) was maintained at 18% O2/ 3% CO2 for 96 hours and behavior was recorded by video. Additionally, horizontal 300 m hippocampal slices were made from five adult animals from two separate colonies. Extracellular recordings of area CA3 pyramidal cells were made under baseline conditions (95% O2/ 5% CO2), and following manipulation of chamber gases. Results: Behavioral observations of naked mole rats under normoxic conditions revealed potential seizure-related behaviors, but no overt seizures were observed. However, when animals were exposed to the inspiratory challenge, robust tonic clonic seizures were observed in multiple adult animals. Hippocampal recordings showed spontaneous epileptiform activity in 16 of 18 slices in all 5 animals. The burst events (amplitude: ~3mV, duration: ~200msec) were very similar to CA3 spontaneous epileptiform burst discharges that develop in the weeks following pilocarpine-induced status epilepticus in rats. Increasing CO2 in the recording chamber stopped the bursting activity after a period of increased frequency, whereas adding N2 to the chamber produced ictal discharges. Stopping the delivery of all gasses (including O2) did not modify the bursts for >20 minutes Conclusions: Our findings suggest that seizures can be induced in the naked mole rat through environmental manipulation designed to mimic burrow conditions in the rainy season, and that the hippocampus produces spontaneous epileptiform activity under routine electrophysiological conditions. Together these data suggest that the naked mole rat is a valuable model for multiple areas of epilepsy research.