Authors: (Rosane Souza da Silva, Giana de Paula Cognato, Alessandra Nejar Bruno, Carla Denise Bonan, Departamento de Biologia Celular e Molecular, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil, and others)
Abstract: During mammalian development, the immature brain is in intense activity of neurogenesis, angiogenesis, and growth of glial cells. A complex net of events is required to achieve the correct brain development, such as the control of neurotransmitter and neuromodulator levels. Nucleotides and nucleosides play a considerable number of trophic effects on neural and vascular cells. ATP signaling is early activated since those P2 purinergic (P2X and P2Y) receptors are expressed at the second week of embryonic development. P2X receptors are transiently expressed in different brain areas. P2X3 appears as the earliest and strongest P2X receptor expressed but their expression decline at later development stages. P2Y receptors in immature brain are early represented by P2Y1 and P2Y4 receptors. The transient expression of P2 receptor matches ectonucleotidases expression. Ectonucleotidase pathway is composed by alkaline phosphatases, ectonucleotide pyrophosphatase/phosphodiesterases (E-NPP), ectonucleoside triphosphate diphosphohydrolases (E-NTPDases), ecto-nucleoside diphosphokinase (E-NDPK) and ecto-5‘-nucleotidase. Alkaline phosphatase family is expressed in human and mousestem cells. E-NPPs are expressed at early embryonic days, such as at embryonic day 9.5 for E-NPP3. However, the expression of E-NPP3 is reduced and restricted to ependymal area in adult brain. NTPDases are expressed in progenitors of neural cells. NTPDase 2 is the dominant ectonucleotidase expressed in these progenitors cells. E-NDPK plays the interconvertion of uridine and adenine nucleotides, serving as important components of the nucleotide metabolism that can control the levels of ATP and other nucleotides in extracellular compartments. Ecto-5‘-nucleotidases are transiently associated with synaptogenesis and became a more glial than neuronal surface enzyme in adult brain. These enzymes play the extracellular metabolism of nucleotides and control the availability of agonists to purinergic receptors. Adenosine, the nucleoside derived from AMP hydrolysis, is an important modulator of neural activity, controlling neuronal firing and blood flow. The levels of extracellular adenosine can also be controlled by bidirectional nucleoside transporters, whose expression and function during brain development are still poorly studied. In rat fetuses, the adenosinergic receptors, named P1, are detected in neural tissues in gestational day 14, but the expression is more prominent at the neonatal period. Formation, maturation, and refinement of synaptic contacts are influenced by neurotransmitters and neuromodulators. Disturbance of normal stimuli during critical periods of neural development can be an important factor to understand different responses to hypoxia and seizures between immature and mature nervous system, as well as underlying drug addiction and neurodegenerative diseases. Control of nucleotides and nucleosides levels by ectonucleotidases, purinergic receptors and nucleoside transporters expression are important key steps to understand the role of nucleotides signaling in developing tissues.