Pharmacological Approaches To Study and Counteract Epileptogenesis in Acquired Epilepsy: Focus on the Role of Microglia

Di Nunzio, Martina (2021). Pharmacological Approaches To Study and Counteract Epileptogenesis in Acquired Epilepsy: Focus on the Role of Microglia. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00013d8f

Abstract

For decades, research on the mechanisms underlying the development of epilepsy has focused mainly on neurons, and more recently research activities have addressed the role of non-neuronal cells, in particular microglia and astrocytes. Microgliosis is a common phenomenon occurring in brain tissue exposed to epileptogenic insults as well as during recurrent seizures in animal models. Microgliosis is also described in brain specimens from human drug-resistant epilepsy foci. This evidence raised the hypothesis that microglia may contribute to pathologic outcomes in epilepsy, such as seizures, neuronal cell loss and neurological comorbidities.

We focused our studies on understanding the temporal pattern of microglia reactivity and proliferation in a murine model of acquired epilepsy, in order to explore whether microglia play a role in epilepsy outcomes. To this aim, CSF1R inhibitors (CSF1Ri), namely PLX3397 and GW2580, were administered to mice undergoing epilepsy development to (1) deplete microglia or (2) to block microglia proliferation, respectively. The results showed that CSF1Ri did not modify synaptic transmission or neuronal excitability, neither prevented epilepsy development. However, CSF1Ri prevented salient neuropathological features of epilepsy, such as structural abnormalities (cortical thinning), neuronal cell loss and cognitive impairment. Notably, blockade of microglial proliferation in mice with already established chronic epilepsy reduced seizures frequency.

Our findings highlight that microglia play distinct roles in distinct disease stages and suggest that timely interference with microglia may attenuate neuronal cell loss and seizures.

Our set of evidence separates cell loss from seizure development in epilepsy and highlights microglia as a cellular target for early neuroprotective intervention. Moreover, since microglial proliferation during the chronic disease stage contributes to seizures, pharmacological interference with this microglia function may offer a potential target for improving seizures control.