Receptor protein tyrosine phosphatase β/ζ regulates loss of neurogenesis in the mouse hippocampus following adolescent acute ethanol exposure

• Published in: Neurotoxicology (Park Forest South) 2023-01, Vol.94, p.98-107
• Main Authors: Galán-Llario, Milagros, Rodríguez-Zapata, María, Gramage, Esther, Vicente-Rodríguez, Marta, Fontán-Baselga, Teresa, Ovejero-Benito, María Carmen, Pérez-García, Carmen, Carrasco, Javier, Moreno-Herradón, Marco, Sevillano, Julio, Ramos-Álvarez, María Pilar, Zapico, José María, de Pascual-Teresa, Beatriz, Ramos, Ana, Herradón, Gonzalo
• Format: Article
• Language: English
• Subjects: Alcohol; Animals; Cytokines - metabolism; Ethanol - toxicity; Female; Hippocampus - metabolism; Male; Mice; Neurogenesis; Neuroinflammation; Neurotoxicity; Pleiotrophin; Receptor-Like Protein Tyrosine Phosphatases, Class 5 - metabolism; Signal Transduction
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2022.11.008

Adolescence is a critical period for brain maturation in which this organ is more vulnerable to the damaging effects of ethanol. Administration of ethanol in mice induces a rapid cerebral upregulation of pleiotrophin (PTN), a cytokine that regulates the neuroinflammatory processes induced by different insults and the behavioral effects of ethanol. PTN binds Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ and inhibits its phosphatase activity, suggesting that RPTPβ/ζ may be involved in the regulation of ethanol effects. To test this hypothesis, we have treated adolescent mice with the RPTPβ/ζ inhibitor MY10 (60 mg/kg) before an acute ethanol (6 g/kg) administration. Treatment with MY10 completely prevented the ethanol-induced neurogenic loss in the hippocampus of both male and female mice. In flow cytometry studies, ethanol tended to increase the number of NeuN+/activated Caspase-3+ cells particularly in female mice, but no significant effects were found. Ethanol increased Iba1+ cell area and the total marked area in the hippocampus of female mice, suggesting sex differences in ethanol-induced microgliosis. In addition, ethanol reduced the circulating levels of IL-6 and IL-10 in both sexes, although this reduction was only found significant in males and not affected by MY10 treatment. Interestingly, MY10 alone increased the total marked area and the number of Iba1+ cells only in the female hippocampus, but tended to reduce the circulating levels of TNF-α only in male mice. In summary, the data identify a novel modulatory role of RPTPβ/ζ on ethanol-induced loss of hippocampal neurogenesis, which seems unrelated to glial and inflammatory responses. The data also suggest sex differences in RPTPβ/ζ function that may be relevant to immune responses and ethanol-induced microglial responses. •RPTPβ/ζ inhibition prevents ethanol-induced adolescent hippocampal neurogenic loss.•RPTPβ/ζ may be involved in microglial responses to ethanol in a sex-dependent manner.•RPTPβ/ζ function may play a role in immune responses in a sex-dependent manner.