A developmental mechanism of temperature-sensitive seizures towards therapeutic manipulation

Children'S Hosp Of Philadelphia, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY Febrile seizures are the most common type of seizure, occurring in 2-4% of all children. Incidence is between 6 months and 3-5 years of age, with a peak between 12-18 months; yet, febrile seizures mysteriously vanish in childhood. While most febrile seizures are benign and self-limited, prolonged febrile seizures are a known risk factor for future epilepsy and can in rare cases be fatal, due to febrile status epilepticus or sudden infant death. Despite the importance of the issue and decades of investigation, a unifying theory has yet to emerge as to the basic mechanism of febrile seizures. Further insight could lead to the development of novel strategies to prevent recurrent febrile seizures in otherwise healthy children and in epilepsy syndromes characterized by recurrent febrile seizures (such as Dravet syndrome), and to anti-epileptogenic therapies after prolonged febrile seizure that could decrease the frequency of temporal lobe epilepsy. This collaborative application employs a comprehensive and multidisciplinary approach and newly-generated tools to test the hypothesis that febrile seizures involve the temperature-dependent failure of action potential generation by a defined subset of GABAergic inhibitory interneuron during a specific developmental window due to a specific vulnerability conferred by a changing balance of sodium and potassium conductances. Proposed experiments will determine the temperature sensitivity of action potential generation and propagation by subsets of GABAergic inhibitory interneurons and excitatory principal cells across relevant brain areas, using biologically-informed computational models to validate experimental findings and generate testable hypotheses (Aim 1). We will demonstrate the same cell type-specific failure during temperature-induced seizures in mice in vivo using two-photon calcium imaging and large scale multiunit electrophysiological recording with Neuropixel probes (Aim 2). Then, we will attempt to attenuate or prevent temperature-sensitive seizures via gene transfer (Aim 3.1) and targeted pharmacotherapy, to rebalance interneuron excitability during this vulnerable developmental window (Aim 3.2). Completion of the proposed experiments will provide novel information as to the developmental trajectory of sodium and potassium ion channel expression as well as the temperature sensitivity of key subtypes of cerebral cortex neurons, to define a novel mechanism of temperature-sensitive seizures across physiologically-relevant experimental models. Such results could drive development of novel treatments or preventative measures for febrile seizures that could reduce associated morbidity and mortality and the future emergence of temporal lobe epilepsy.