Bredewold Remco, Washington Catherine, Veenema Alexa H
Neurobiology of Social Behavior Laboratory, Department of Psychology and Neuroscience Program, Michigan State University, East Lansing, MI, USA.
Neuropsychopharmacology. 2025 Mar;50(4):630-639. doi: 10.1038/s41386-024-01987-z. Epub 2024 Sep 20.
Understanding the neural basis of social play in juvenile rats may ultimately help restore social play deficits in autistic children. We previously found that administration of a vasopressin (AVP) V1a receptor (V1aR) antagonist into the lateral septum (LS) increased social play behavior in male juvenile rats and decreased it in females. Here, we demonstrate that glutamate, but not GABA, is involved in this sex-specific regulation. First, we found a sex difference in extracellular LS glutamate/GABA ratio (lower in females) that was eliminated by V1aR antagonist infusion in the LS that caused an increase in glutamate release in females only. Second, infusion of the glutamate receptor agonist L-glutamic acid into the LS mimicked the V1aR antagonist-induced decrease in female social play while preventing the increase in male social play. Third, infusion of the glutamate receptor antagonists AP-5 and CNQX into the LS prevented the V1aR antagonist-induced decrease in female social play. Fourth, there were no sex differences in extracellular GABA release in the LS upon either V1aR antagonist infusion or in social play expression upon infusion of the GABA-A receptor agonist muscimol into the LS, suggesting that GABA is not involved in the sex-specific regulation of social play by the LS-AVP system. Last, we found no sex differences in the type (GAD1/2, somatostatin, calbindin 1, Sox9) of V1aR-expressing LS cells, suggesting other cellular mechanisms mediating the sex-specific effects on glutamate release in the LS by the LS-AVP system. In conclusion, we demonstrate that the LS-AVP system regulates social play sex-specifically via glutamatergic neurotransmission. These findings have relevance for potential sex-specific effects of AVP-based treatment of social deficits in children.
了解幼年大鼠社交玩耍的神经基础最终可能有助于恢复自闭症儿童的社交玩耍缺陷。我们之前发现，向外侧隔区（LS）注射血管加压素（AVP）V1a受体（V1aR）拮抗剂可增加雄性幼年大鼠的社交玩耍行为，而减少雌性大鼠的社交玩耍行为。在此，我们证明谷氨酸而非GABA参与了这种性别特异性调节。首先，我们发现LS细胞外谷氨酸/GABA比值存在性别差异（雌性较低），而在LS中注射V1aR拮抗剂可消除这种差异，该拮抗剂仅导致雌性谷氨酸释放增加。其次，向LS中注射谷氨酸受体激动剂L - 谷氨酸可模拟V1aR拮抗剂诱导的雌性社交玩耍减少，同时阻止雄性社交玩耍增加。第三，向LS中注射谷氨酸受体拮抗剂AP - 5和CNQX可阻止V1aR拮抗剂诱导的雌性社交玩耍减少。第四，无论是注射V1aR拮抗剂还是向LS中注射GABA - A受体激动剂蝇蕈醇后，LS细胞外GABA释放均无性别差异，这表明GABA不参与LS - AVP系统对社交玩耍的性别特异性调节。最后，我们发现表达V1aR的LS细胞类型（谷氨酸脱羧酶1/2、生长抑素、钙结合蛋白1、Sox9）不存在性别差异，这表明存在其他细胞机制介导LS - AVP系统对LS中谷氨酸释放的性别特异性影响。总之，我们证明LS - AVP系统通过谷氨酸能神经传递对社交玩耍进行性别特异性调节。这些发现与基于AVP治疗儿童社交缺陷的潜在性别特异性效应相关。
