Pleiotrophin Overexpression Reduces Adolescent Ethanol Consumption and Modulates Ethanol‐Induced Glial Responses and Changes in the Perineuronal Nets in the Mouse Hippocampus.

Aims: To investigate whether pleiotrophin (PTN) overexpression influences ethanol consumption during adolescence and its effects on glial responses, neurogenesis, and perineuronal nets (PNNs) in the mouse hippocampus. Methods: Male and female adolescent transgenic mice with elevated PTN levels (Ptn‐Tg) and controls underwent an intermittent access to ethanol (IAE) 2‐bottle choice protocol. Ethanol consumption, PTN levels, neurogenesis, and glial responses were measured in the hippocampus. Immunohistochemistry was used to assess changes in new neurons, microglial and astrocyte populations, and PNNs. Results: Ptn‐Tg mice consumed significantly less ethanol compared to controls, irrespective of sex. Chronic alcohol exposure reduced PTN levels in the hippocampus. PTN overexpression decreased the number of new neurons in the dentate gyrus (DG) and prevented ethanol‐induced microglial activation. Ptn‐Tg mice had significantly more astrocytes and fewer PNNs, with a higher percentage of parvalbumin (PV) positive cells surrounded by PNNs under basal conditions. However, ethanol drastically reduced the number of PV+ cells in the DG of Ptn‐Tg mice, despite the presence of PNNs. Conclusion: PTN overexpression reduces adolescent ethanol consumption and influences ethanol‐induced effects on hippocampal neurogenesis, glial responses, and PNN remodeling. These findings underscore the importance of PTN in modulating alcohol‐induced neurotoxicity. [ABSTRACT FROM AUTHOR]