Investigating the role of NG2-glia in the development of epilepsy

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Project Summary According to the CDC, there are more than 3 million people with active epilepsy in the US. It is estimated that up to 50% of all epilepsy cases are initiated by a neurological insult and are called acquired epilepsy. Brain infections and traumatic brain injury are two major examples of common brain injuries that can lead to the development of acquired epilepsy. Although there is diversity in the etiology and the severity of the disorder, understanding the cellular and molecular mechanisms by which seizures develop will aid in uncovering novel ways to prevent epilepsy following high-risk CNS injuries. Evidence has accumulated indicating that glial cells play an important role in the initiation and maintenance of the prolonged neuroplasticity changes underlying the development of epilepsy. NG2-glia are commonly known as oligodendrocyte progenitor cells (OPCs). However, a growing body of evidence has led to their classification as a major glial cell-type in their own right. Recent evidence suggests that these cells play important roles in maintaining environmental homeostasis, and disruptions to NG2-glia function have now been highly implicated in the development and progression of neurologic disease. To investigate whether NG2-glia are involved in epilepsy development, in Aim 1, NG2-glia morphology, structural organization, and protein expression were evaluated in a viral infection-induced mouse model of acquired epilepsy. The analysis identified that NG2-glia have highly reactive morphology, increased proliferation, and are involved in scar formation both during viral infection and following viral clearance. These NG2-glia responses are also highly localized to the hippocampus, the site of active infection and the origin site of seizures. This is significant because, while likely triggered by the initiating infection, the NG2-glia reaction may continue to play an important role in long-term neuroplasticity deficits that lead to epilepsy. Preliminary experiments in Aim 2 demonstrate that extracellular purines (damage signals that are heavily produced in the hippocampus following viral infection) induce robust elevations in intracellular calcium in NG2- glia. This finding is important because calcium can be used as a functional readout to better understand the real- time dynamics and the environmental signals initiating the NG2-glia reaction to injury and infection. Future work aims to use calcium signaling as a functional readout combined with morphological changes to better understand the intracellular and intercellular communication that occurs between glial cells during injury and disease. This study is the first to analyze calcium signaling in NG2-glia during infection and epilepsy development, and may lead to novel cellular and molecular targets to restore homeostasis and prevent the development of epilepsy following a high-risk insult to the central nervous system.