Glial activation links early-life seizures and increased susceptibility to seizures in adulthood</Public Deposited
Early-life seizures increase susceptibility to seizures in adulthood. However, mechanisms by which seizures in the developing brain lead to increased vulnerability to seizures and exacerbation of neurological injury in adulthood remain unknown. We test the hypothesis that upregulation of proinflammatory cytokine levels and chronic glial activation following early-life seizures result in increased susceptibility to seizures and greater neurological injury in adulthood. We first demonstrate that kainic acid (KA)-induced early-life seizures in a rat model result in acute increase in proinflammatory cytokines and chronic astrocyte activation associated with hippocampal-dependent behavioral impairment. The early glial activation response precedes the appearance of neuronal injury. Next, we show that post-injury treatment with the novel aminopyridazine anti-inflammatory compound, Minozac (Mzc), suppresses the upregulation of proinflammatory cytokines, attenuates prolonged astrocyte activation, and improves behavioral deficits following early-life seizures. Utilizing the 'two-hit' model of KA-induced seizures, we demonstrate that upregulation of proinflammatory cytokines and chronic astrocyte activation following early-life seizures prime microglia for enhanced and greater microglial activation response to subsequent seizures in adulthood. The greater increase in proinflammatory cytokines following a 'second hit' of seizures in adulthood compared to early-life response is accompanied by earlier onset of seizures, greater severity of seizures, hippocampal-linked behavioral impairment, more extensive increase in neuronal injury, and enhanced microglial activation. Thus, the glial activation response following early-life seizures renders the brain more vulnerable to seizures and neuronal injury in adulthood. The suppression of enhanced microglial activation responses, concomitant reduction in neuronal injury, and prevention of increased susceptibility to seizures by treatment with Mzc following early-life seizures provide direct evidence of the mechanistic link between glial activation, microglial priming, neuronal dysfunction, and seizure susceptibility. The efficacy of Mzc in preventing the long-term neurologic sequelae of early-life seizures in these studies is further evidence in support of glial activation as a therapeutic target in neurological disorders. Overall, the results establish a role for glial activation as a susceptibility factor for subsequent neurological injury.