Dual role of the P2X7 receptor in dendritic outgrowth during physiological and pathological brain development.

At high levels, extracellular ATP operates as a "danger" molecule under pathological conditions through purinergic receptors, including the ionotropic P2X7 receptor (P2X7R). Its endogenous activation is associated with neurodevelopmental disorders; however, its function during early embryonic stages remains largely unclear. Our objective was to determine the role of P2X7R in the regulation of neuronal outgrowth. For this purpose, we performed Sholl analysis of dendritic branches on primary hippocampal neurons and in acute hippocampal slices from wild-type (WT) mice and mice with genetic deficiency or pharmacological blockade of P2X7R. Because abnormal dendritic branching is a hallmark of certain neurodevelopmental disorders, such as schizophrenia, a model of maternal immune activation (MIA)-induced schizophrenia was used for further morphological investigations. Subsequently, we studied MIA-induced behavioral deficits in young adult mice females and males. Genetic deficiency or pharmacological blockade of P2X7R led to branching deficits under physiological conditions. Moreover, pathological activation of the receptor led to deficits in dendritic outgrowth on primary neurons from WT mice but not those from P2X7R knockout (KO) mice exposed to MIA. Likewise, only MIA-exposed WT mice displayed schizophrenia-like behavioral and cognitive deficits. Therefore, we conclude that P2X7R has different roles in the development of hippocampal dendritic arborization under physiological and pathological conditions.Our main finding is a novel role for P2X7R in neuronal branching in the early stages of development under physiological conditions. We show how a decrease in the expression of P2X7R during brain development causes the receptor to play pathological roles in adulthood. Moreover, we studied a neurodevelopmental model of schizophrenia and found that at higher ATP concentrations, endogenous activation of P2X7R is necessary and sufficient for the development of positive and cognitive symptoms.