Authors :
Presenting Author: Ayesha Alkofahi, MS – Southern Methodist University
Fallon Wenck, MS – Southern Methodist University
Indumathy Jagadeeswaran, PhD – Southern Methodist University
Praveen Kumar, PhD – Southern Methodist University
Kelsey Paulhus-Halvorson, PhD – Southern Methodist University
Edward Glasscock, PhD – Southern Methodist University
Rationale:
Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of epilepsy-related mortality, yet its mechanisms and risk factors are poorly understood. Increasing evidence implies that autonomic dysfunctions, including impairments in cardiorespiratory functions and thermoregulation, can influence SUDEP susceptibility. To investigate these mechanisms, we studied the Kv1.1 knockout (KO) mouse, which lacks the voltage-gated potassium channel alpha subunit Kv1.1. Kv1.1 regulates action potential shape and neuronal firing; its absence causes hyperexcitability. As a result, Kv1.1 KO mice display spontaneous seizures and premature death, making them a widely used SUDEP model. While prior studies have identified cardiac and respiratory abnormalities, thermoregulation in this model remains understudied. Previous literature has described cold swim-induced seizures in KO mice suggesting that altered thermoregulation may increase seizure susceptibility. However, whether these mice show broader temperature sensitivity and thermoregulatory failure, like other SUDEP models, remains unknown. Here, we evaluated body temperature dynamics and thermal stress-induced behaviors in global and conditional Kv1.1 KO mice. By characterizing thermoregulatory control in this model, we aim to uncover mechanisms and predictive biomarkers of SUDEP that may support the development of future preventive therapeutic strategies.Methods:
Kv1.1 global (KO) and conditional knockout (cKO) mice (P27-P31), along with wildtype (WT) and heterozygous (Het) controls, were implanted with intraperitoneal transponders to monitor core body temperature and activity. For heat stress, baseline was recorded for 30 minutes, followed by exposure to 30°C (mild) or a stepwise increase to 41.5°C (high) using an infrared lamp, with a 30-minute recovery. For cold stress, mice swam in 17°C water for 1 minute, then recovered for 90 minutes while temperature and behavior were monitored. For EEG, subdural cortical electrodes were implanted, and recordings were taken before and after high-heat stress.Results:
Baseline temperature was unchanged across genotypes. After the cold swim, KO mice (n=12) showed a significantly larger drop in body temperature and slower recovery compared to WT (n=11) and Het (n=22) (p=0.0061). Global and corticolimbic cKO mice (n=5) exhibited cold swim seizures. During mild heat, KO mice (n=6) had significantly greater peak temperature increases than WT (n=8) and Het (n=8) (p=0.0018). Following high heat, KO mice (n=6) displayed seizure-like behaviors during recovery without corresponding EEG abnormalities.Conclusions:
Kv1.1 KO mice display previously unrecognized thermoregulatory deficits, revealing a novel role for Kv1.1 in autonomic homeostasis. Kv1.1 cKOs implicate the corticolimbic circuit in thermoregulation, providing the first evidence linking forebrain networks to cold swim seizures. Similar to what is known about cold swim seizures, seizure-like behaviors during recovery from heat occur without epileptiform EEG activity, suggesting shared mechanisms. Identifying the circuits underlying these dysfunctions and seizures may help identify predictive biomarkers for SUDEP.Funding:
NIH (R01NS129643 to E.G.)