TRPV1 deletion exacerbates hyperthermic seizures in an age-dependent manner in mice

Abstract

Febrile seizures (FS) are the most common seizure disorder to affect children. Although there is mounting evidence to support that FS occur when children have fever-induced hyperventilation leading to respiratory alkalosis, the underlying mechanisms of hyperthermia-induced hyperventilation and links to FS remain poorly understood. As transient receptor potential vanilloid-1 (TRPV1) receptors are heat-sensitive, play an important role in adult thermoregulation and modulate respiratory chemoreceptors, we hypothesize that TRPV1 activation is important for hyperthermia-induced hyperventilation leading to respiratory alkalosis and decreased FS thresholds, and consequently, TRPV1 KO mice will be relatively protected from hyperthermic seizures. To test our hypothesis we subjected postnatal (P) day 8-20 TRPV1 KO and C57BL/6 control mice to heated dry air. Seizure threshold temperature, latency and the rate of rise of body temperature during hyperthermia were assessed. At ages where differences in seizure thresholds were identified, head-out plethysmography was used to assess breathing and the rate of expired CO₂ in response to hyperthermia, to determine if the changes in seizure thresholds were related to respiratory alkalosis. Paradoxically, we observed a pro-convulsant effect of TRPV1 deletion (∼4min decrease in seizure latency), and increased ventilation in response to hyperthermia in TRPV1 KO compared to control mice at P20. This pro-convulsant effect of TRPV1 absence was not associated with an increased rate of expired CO₂, however, these mice had a more rapid rise in body temperature following exposure to hyperthermia than controls, and the expected linear relationship between body weight and seizure latency was absent. Based on these findings, we conclude that deletion of the TRPV1 receptor prevents reduction in hyperthermic seizure susceptibility in older mouse pups, via a mechanism that is independent of hyperthermia-induced respiratory alkalosis, but possibly involves impaired development of thermoregulatory mechanisms, although at present the mechanism remain unknown.

Keywords: Age-dependent; Febrile seizures; Rate of expired CO(2); Respiratory alkalosis; Ventilation.