Abstracts

Rationale: Febrile seizures are the most common type of seizure in infancy and early childhood. Hyperthermia (>38 oC) alone is sufficient to induce febrile seizures in murine models in vivo and in vitro. The cellular mechanisms by which high temperature triggers seizures in the immature brain are very poorly understood. Previously, we demonstrated that heating the solution bathing in vitro brain slices increases multiunit activity in CA3. Here we examined how hyperthermia alters the physiological properties of pyramidal cells and stratum oriens interneurons in mouse hippocampal area CA3 in vitro. Methods: We made whole-cell current clamp recordings in CA3 pyramidal cells and CA3 stratum oriens interneurons to measure changes in intrinsic membrane properties and spontaneous firing patterns during heating of the perfusion solution from 30°C to 42°C. Results: Under current-clamp, warming from 30°C to 42°C induced depolarizations of about 15-40 mV in CA3 pyramidal cells. Heating also decreased input resistance (25-50%) and membrane time-constant (40-60%), and increased spontaneous synaptic activity and spike firing in most pyramidal cells. High temperature induced many pyramidal cells to switch from tonic- to burst-spiking mode, and in strongly depolarized cells the spikes were inactivated. Most of the effects of these brief epochs of heating (<5 min) were reversible in the majority of cells. The effects of febrile temperature on the intrinsic membrane properties of inhibitory interneurons have not been reported. We compared the effects of hyperthermia on the excitability of interneurons in stratum oriens of CA3 to the effects observed in CA3 pyramidal neurons. Heating induced membrane depolarizations of about 10-20 mV (less than in pyramidal cells), decreased interneuron input resistances and membrane time constants, and increased spontaneous synaptic inputs (similar to pyramidal cells). Hyperthermia induced spontaneous spiking of interneurons less often than in pyramidal cells, and spontaneous firing rates of interneurons were much lower than firing rates of pyramidal cells. We are currently testing the interneuron subtype-dependence of hyperthermia-induced physiological changes. Conclusions: Our results demonstrate that hyperthermia increases the excitability of both pyramidal cells and stratum oriens interneurons in CA3, though with some notable differences. These differences may lead to an imbalance of excitation and inhibition, thereby increasing the likelihood of epileptiform activity.