The P2X7 receptors and the growth of pyramidal neurons in the hippocampus

In a landmark study, researchers from the Laboratory of Molecular Pharmacology led by Beata Sperlagh, in collaboration with the Universidad Autonóma de Madrid, have shown a direct link between the P2X7 purinergic receptor and the growth and sprouting of pyramidal neurons in the hippocampus, the brain region best known for its memory-related processes. The discovery could be crucial to understanding the mechanisms of brain formation that often underlie the critical period of normal brain development. The study was published in the prestigious Nature Index periodical, The Journal of Neuroscience. 

Pyramidal cells, or pyramidal neurons, are found in many areas of the brain and undergo many rapid changes during early postnatal life. Purinergic signaling is a form of signaling mediated by purines, including ATP and its breakdown products, which activate purinergic receptors in cells, thereby regulating cellular functions.

Inflammatory processes also play a crucial role in altered brain function and in the development of neurological diseases and disorders such as stroke, Alzheimer's disease, Parkinson's disease, epilepsy, dementia, and neurodevelopmental disorders. Neurodevelopmental disorders such as autism and schizophrenia are thought to be the result of abnormal inflammatory events at critical points in brain development. The goal of the research was to establish whether the P2X7 receptor could act as a therapeutic target in these disorders to reduce the susceptibility of adolescents and young individuals to develop these symptoms.

This newly published study demonstrates the effect of P2X7R regulation on neuronal growth and morphology in primary cultures of mouse hippocampal neurons and acute hippocampal slices. The researchers also examined dendritic morphology in a mouse model of schizophrenia. They have also studied the link between abnormal dendritogenesis and human pathologies to determine whether P2X7R, a major player in inflammatory events in the brain under pathological conditions, plays a regulatory role in the complex pathomechanism of psychiatric disorders.

The researchers have described a novel role for P2X7R in the small window of time during early pregnancy that is required for the proper development of pyramidal cells. Genetically engineered mice lacking the P2X7 receptor showed poorer performance in memory tests in adolescence. Similarly, abnormal activation of the P2X7 receptor, which may be a consequence of inflammatory processes during pregnancy, had a similar detrimental effect on neurodevelopment. 

Similar to the deficits observed in human patients in adulthood, a susceptibility to performance deterioration has been observed in a mouse model of schizophrenia in several tests. Taken together, this suggests a specific role for the P2X7 receptor, which requires that for healthy brain development, the receptor must be present in a strictly balanced manner during gestation.
The first author, Paula Mut Arbona, used immunostaining of primary hippocampal cultures, confocal microscopy, and ex vivo studies, and the laboratory of Professor Antonio García (Teófilo Hernando Foundation) was involved in the synthesis of a new P2X7 antagonist ligand. Using a multifaceted approach, in vivo behavioral experiments, and disease models in mice, the researchers have demonstrated a key physiological and pathophysiological role for receptor activity. 

Beáta Sperlágh's group has pioneered the description of the role of purinergic signaling in the central nervous system. Over the last twenty years, new purinergic drug targets have been successfully identified in depression, schizophrenia, and several other neurodevelopmental disorders.

The importance of this discovery is illustrated by the fact that either blocking the receptor or pathologically inhibiting the receptors prevents the development of the characteristic cortical structure. Therefore, purinergic signaling should be considered a fundamental therapeutic target for neurodevelopmental disorders and other diseases.