Seizures in neonates are a vexing clinical problem with lack of consensus on diagnosis and treatment goals. The problem is further compounded by the disappointing efficacy of currently available anti-seizure drugs. The lack of progress in improving treatment algorithms for these patients is partly due to an incomplete understanding of the mechanisms underlying seizure generation in an immature brain. While a large amount of research has focused on excitatory to inhibitory synaptic transmission imbalance, the knowledge gained in this area has failed to lead to more effective or safer therapies for neonates with seizures. Kainate receptors are a class of receptors mediating excitation in the brain that have recently been the subject of increased scrutiny for their role in the pathophysiology of seizures. They are abundantly expressed in the brain of neonatal animals and have diverse functions important to the regulation of neuronal network activity. Gaps in knowledge remain in the understanding of their role in modulating response to hypoxia and seizure generation in the neonatal period. Our preliminary data suggest that activation of kainate receptors during hypoxia enhances excitatory and decreases inhibitory synaptic transmission in neonatal mice. Further, pre-treatment with a kainate receptor antagonist decreases susceptibility to hypoxic seizures in these mice. In this proposal we aim to expand on this preliminary data and further characterize the role of these receptors in modulating susceptibility to hypoxic seizures in neonatal mice by testing the hypothesis that activation of kainate receptors by glutamate during hypoxia alters synaptic transmission leading to increased seizure susceptibility in the neonatal mouse. To address this question, we will first characterize kainate receptor-mediated modulation of excitatory and inhibitory synaptic transmission during hypoxia using patch-clamp electrophysiology techniques in wild-type and GluK-2 knockout neonatal mice (Aim 1). We will then investigate the role of kainate receptor on seizure susceptibility following hypoxia in wild-type and GluK2 knockout neonatal mice. The effects of hypoxia on neuronal activation in the neonatal mouse hippocampus will also be evaluated using the Ca++ indicator GCaMP6 (Aim 2). Relevance to the mission of the agency: The proposed studies will further our understanding of the role kainate receptor in the pathophysiology of early-life seizures and may help delineate novel therapeutic targets. Results from these studies will advance our understanding of the epileptogenic process involved with epilepsies of neurodevelopmental origins, a goal highlighted in the consensus-derived NINDS ?2014 Benchmarks for Epilepsy Research? statement.
Neonatal seizures are common and remain a frustrating clinical challenge with little agreement on diagnosis or treatment goals; a problem further compounded by the disappointing efficacy of currently available anti-seizure medications. The lack of progress in improving treatment algorithms and outcomes for these patients is partly due to an incomplete understanding of the mechanisms underlying seizure generation in an immature brain, particularly in the acute phase. The goal of this proposal is to explore a novel hypothesis that kainate receptors, which are highly expressed in the neonatal brain, play an important role in response to hypoxia and seizure generation in the developing brain.
