Investigating the role of brainstem neuroinflammation in cardiorespiratory control in a rat model of recurrent epilepsy

点击翻译按钮获取中文摘要

Abstract: Epilepsy is one of the most common neurological conditions in the world. Treatment with anti-epileptic drugs (AEDs) prevent recurrent seizures in ~70% of patients with epilepsy, but the remaining 30% of patients with refractory epilepsies continue to experience uncontrolled seizures. The negative consequences of repeated seizures include post-ictal cardiorespiratory suppression putting these patients at high risk of Sudden Unexpected Death in Epilepsy (SUDEP). Fundamental knowledge gaps exist in our understanding of how repeated seizures disrupt the vital cardiorespiratory control systems in the brain. A factor commonly identified in many neurological conditions including epilepsy is neuroinflammation, which supports beneficial functions in health but is dysregulated in epilepsy patients and animal models of seizure disorder. Key cells within the CNS mediating pathological neuroinflammation are resident microglia and astrocytes, which have also been shown to be dysfunctional in human epilepsy. However, it is not known what mechanistic role the glial-derived neuroinflammation plays in the impairment of cardiorespiratory control or increased SUDEP risk. Here, I hypothesize that repeated seizures lead to activation of neuroinflammation mediated by microglia within key brainstem regions controlling cardiorespiratory function causing a progressive decline in these vital functions. Published and preliminary data in our novel rat model with genetic mutations in a gene (kcnj16) encoding an inwardly-rectifying potassium ion channel (Kir5.1; SSkcnj16-/- rats) show that repeated sound-induced seizures (1/day for up to 10 days) lead to progressively more severe post-ictal cardiorespiratory suppression and unexpected mortality particularly in male rats. Through snRNA sequencing and bioinformatic pathway analyses of transcriptomic changes specifically within microglial cells in the medullary raphe (key breathing control region) identified significant predicted activation of IL-1ß signaling following repeated seizures, consistent with immunofluorescent brainstem tissue analyses. Here I propose two Specific Aims which: 1) characterize cell- specific transcriptomic shifts in gene expression within key cardiorespiratory control regions to identify key cells types and pathways mediating local neuroinflammation leading to neuronal dysfunction, and 2) functionally test the roles of microglia and IL-1 signaling in the brain in mediating the progressive cardiorespiratory suppression and/or unexpected seizure-induced mortality. Identifying neuroinflammatory signals/pathways induced by repeated seizures within distinct neural circuits in our novel rat model will enhance our understanding of the pathophysiological consequences of uncontrolled seizures in patients with refractory epilepsy, and hold the potential for identifying new therapeutic targets aimed at preventing seizure-induced cardiorespiratory dysfunction function and reduce SUDEP risk.