The neuronal P2X7R controversy: Revisiting evidence, methods, and unresolved questions

The P2X7 receptor (P2X7R) is an ATP-gated ion channel belonging to the purinergic ligand-gated P2X receptor family. In the central nervous system (CNS), activation of this receptor has been proposed to play a key role in the pathogenesis of various neurodegenerative disorders. Its expression has been clearly demonstrated in microglia, where it regulates numerous cellular processes, including cell activation, cytokine release, and calcium signaling. Recent data show convincing arguments for the presence of P2X7R also in other cell types of the nervous system, such as astrocytes, oligodendrocytes, oligodendrocyte progenitor cells (OPCs) and neural progenitor cells (NPCs), although there is still some debate. The most controversial, however, is the presence and role of P2X7R in neurons. In this review, we aim to critically address this question by examining the current literature in the context of the available tools. We revisit the pharmacological regimen required to confirm the functional expression of the receptor and the mouse models that have aided in the investigation of neuronal P2X7R. Finally, we discuss some of the hypothesized contributions of neuronal P2X7R in CNS disorders.