Targeting the purinergic P2X7 receptor in epilepsy: Cell types matter

Epilepsy affects up to 70 million people worldwide, making it one of the most prevalent chronic neurological disorders and a major burden on healthcare systems. Although more than 30 anti-seizure medications (ASMs) are currently in clinical use, drug refractoriness remains a major clinical challenge. In addition, ASMs often cause life quality-reducing side effects and do not significantly modify the underlying course of the disease. Purinergic signalling mediated by extracellular ATP has gained increasing attention as a contributor to seizures and epilepsy, particularly through activation of the ionotropic P2X7 receptor (P2X7R). Accumulating evidence demonstrates that P2X7R antagonism can modulate acute seizures and reduce the seizure burden in epilepsy. Given the prominent expression of P2X7Rs on immune cells such as microglia, P2X7R-dependent effects on seizures have mainly been attributed to the initiation of proinflammatory signalling cascades. Consistent with this, studies have reported reduced seizure severity in mice lacking microglial P2X7Rs, and P2X7R-induced inflammatory responses have been implicated in resistance to pharmacotherapy. However, P2X7Rs participate in a wide range of pathological cellular processes, therefore, restricting their contribution to hyperexcitability and epilepsy solely to inflammation likely represents an oversimplification. In this line, emerging research indicates that P2X7R signalling exerts cell type-specific effects, with both pro- and anticonvulsive functions depending on the cellular context. The main aim of this review is to provide a critical discussion of the role of P2X7Rs in epilepsy, with a particular focus on their potential cell type-specific contributions.