Epilepsy represents a neurological disorder that can manifest in uncontrolled seizures in patients. Microglia are exquisitely sensitive to disruptions i the central nervous system. Since epilepsy is characterized by neuronal hyperactivity activity rooted in excessive glutamate release and ionic imbalance, it is conceivable that microglia may perform functions to reduce neuronal dysfunction and promote neuronal health during the pathology. In our preliminary studies, we have found that microglia respond by robust process extension making increasing contact with neurons during elevated glutamate levels in acute brain slices. Moreover, in three different models of epileptiform activity, microglial processes focus on neuronal dendrites and microglial ablation reduces behavioral seizure scores. Based on our preliminary results, we hypothesize that during increased glutamate levels hyperactive neurons signal to microglia inducing their process extension. Additionally, during hyperactive neuronal activity, microglial processes focus on neuronal elements with a consequence to downregulate such hyperactivity which is critical in limiting behavioral seizure outcome and promoting neuronal survival. We will now test this hypothesis along with the following specific aims.
In Aim 1, we will determine the underlying mechanisms behind glutamate-induced microglial process extension elucidating the neuronal receptors initiating and the released chemoattractants mediating the process extension signal.
In Aim 2, we will determine the targets of microglial process focus as well as the chemoattractants mediating the response in three models of epileptiform activity in acute brain slices.
In Aim 3, we will extend our observations in acute brain slices to in vivo live brain and determine the role of microglia in epilepsy-induced seizure behaviors and neuronal cell death by microglial ablation and genetic deletion of the unique microglial P2Y12 receptor. These studies are the first to investigate the microglial dynamics during acute epilepsy. They will increase our understanding of the mechanisms underlying microglial-neuronal interactions during epileptic activity and the neuroprotective potential of microglia in epilepsy. In addition, the outcome of these studies will provide new data that could inform the development of novel therapies in the treatment of epileptic disorders.
The current proposal aims to determine the activities and function of microglia during hyperactive neuronal activity as occurs during epilepsy. Specifically, the experiments outlined in the proposal will enhance our understanding of the mechanisms underlying microglial-neuronal interactions during epileptic activity and the neuroprotective potential of microglia during epilepsy. The outcome of these studies may potentially inform new strategies in the development of therapy against epileptic disorders.
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