Adolescence is a critical period for brain maturation in which this organ undergoes critical plasticity mechanisms that increase its vulnerability to the effects of alcohol. Significantly, ethanol-induced disruption of hippocampal neurogenesis has been related to cognitive decline in adulthood. During adolescence, the maturation of perineuronal nets (PNNs), extracellular matrix structures highly affected by ethanol consumption, plays a fundamental role in neurogenesis and plasticity in the hippocampus. Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ is a critical anchor point for PNNs on the cell surface. Using the adolescent intermittent access to ethanol (IAE) model, we previously showed that MY10, a small-molecule inhibitor of RPTPβ/ζ, reduces chronic ethanol consumption in adolescent male mice but not in females and prevents IAE-induced neurogenic loss in the male hippocampus. We have now tested if these effects of MY10 are related to sex-dependent modulatory actions on ethanol-induced effects in PNNs. Our findings suggest a complex interplay between alcohol exposure, neural structures, and sex-related differences in the modulation of PNNs and parvalbumin (PV)-positive cells in the hippocampus. In general, IAE increased the number of PV + cells in the female hippocampus and reduced PNNs intensity in different hippocampal regions, particularly in male mice. Notably, we found that pharmacological inhibition of RPTPβ/ζ with MY10 regulates ethanol-induced alterations of PNNs intensity, which correlates with the protection of hippocampal neurogenesis from ethanol neurotoxic effects and may be related to the capacity of MY10 to increase the gene expression of key components of PNNs.

青春期是大脑成熟的关键时期，这个器官经历了关键的可塑性机制，增加了其对酒精影响的脆弱性。值得注意的是，乙醇引起的海马神经发生破坏与成年期认知能力下降有关。在青春期，神经周围网（PNN）的成熟，即受乙醇消耗高度影响的细胞外基质结构，在海马体的神经发生和可塑性中发挥着重要作用。受体蛋白酪氨酸磷酸酶 (RPTP) β/ζ 是细胞表面 PNN 的关键锚点。使用青少年间歇性获取乙醇（IAE）模型，我们之前表明，MY10（一种 RPTPβ/ζ 的小分子抑制剂）可减少青春期雄性小鼠的慢性乙醇消耗，但不会减少雌性小鼠的慢性乙醇消耗，并防止 IAE 诱导的雄性小鼠神经源性损失海马体。我们现在已经测试了 MY10 的这些作用是否与 PNN 中乙醇诱导作用的性别依赖性调节作用有关。我们的研究结果表明，酒精暴露、神经结构以及海马 PNN 和小白蛋白 (PV) 阳性细胞调节中的性别相关差异之间存在复杂的相互作用。一般来说，IAE 增加了雌性海马中 PV + 细胞的数量，并降低了不同海马区域的 PNN 强度，特别是在雄性小鼠中。值得注意的是，我们发现 MY10 对 RPTPβ/ζ 的药理学抑制可调节乙醇诱导的 PNN 强度改变，这与保护海马神经发生免受乙醇神经毒性作用相关，并可能与 MY10 增加关键基因表达的能力有关。 PNN 的组成部分。