Dual Role of the P2X7 Receptor in Dendritic Outgrowth during Physiological and Pathological Brain Development

Mut-Arbona, Paula and Huang, Lumei and Baranyi, Mária and Tod, Pál and Iring, András and Calzaferri, Francesco and de los Ríos, Cristobal and Sperlágh, Beáta (2023) Dual Role of the P2X7 Receptor in Dendritic Outgrowth during Physiological and Pathological Brain Development. JOURNAL OF NEUROSCIENCE, 43 (7). pp. 1125-1142. ISSN 0270-6474

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Abstract

At high levels, extracellular ATP operates as a “danger” molecule under pathologic 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 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 morphologic 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, pathologic activation of the receptor led to deficits in dendritic outgrowth on primary neurons from WT mice but not those from P2X7R 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 pathologic conditions.

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