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Updated: Mar 12, 2026
A Behavioral Screen for Heat-Induced Seizures in Mouse Models of Epilepsy
Published on: July 12, 2021
TRPV1 deletion exacerbates hyperthermic seizures in an age-dependent manner in mice
Karlene T Barrett1, Richard J A Wilson2, Morris H Scantlebury3
1Department of Pediatrics, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
Insights
Transient receptor potential vanilloid-1 (TRPV1) deletion paradoxically increased seizure susceptibility in young mice. This effect was linked to faster body temperature rise, not respiratory alkalosis, suggesting impaired thermoregulation.
Area of Science:
- Neuroscience
- Physiology
- Developmental Biology
Background:
- Febrile seizures (FS) are common in children, potentially linked to fever-induced hyperventilation and respiratory alkalosis.
- The precise mechanisms of hyperthermia-induced hyperventilation and its connection to FS are not fully understood.
- Transient receptor potential vanilloid-1 (TRPV1) receptors are heat-sensitive and involved in thermoregulation and respiratory control.
Purpose of the Study:
- To investigate the role of TRPV1 activation in hyperthermia-induced hyperventilation, respiratory alkalosis, and febrile seizure thresholds.
- To determine if TRPV1 knockout (KO) mice are protected from hyperthermic seizures.
Main Methods:
- Postnatal day 8-20 TRPV1 KO and control mice were exposed to heated dry air.
- Seizure threshold temperature, latency, and body temperature rise rate were measured.
- Head-out plethysmography assessed breathing and expired CO2 to evaluate respiratory alkalosis.
Main Results:
- TRPV1 deletion showed a pro-convulsant effect, decreasing seizure latency in P20 mice.
- TRPV1 KO mice exhibited increased ventilation but not altered expired CO2 during hyperthermia.
- TRPV1 KO mice displayed a more rapid rise in body temperature compared to controls.
Conclusions:
- TRPV1 deletion does not protect against hyperthermic seizures in older mouse pups and may increase susceptibility.
- The pro-convulsant effect is independent of respiratory alkalosis, suggesting a role for impaired thermoregulation.
- Further research is needed to elucidate the exact mechanisms underlying TRPV1's role in thermoregulation and seizure susceptibility.
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.
