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Vasopressin regulates social play behavior in sex-specific ways through glutamate modulation in the lateral septum

Neuropsychopharmacology (2024)Cite this article

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Abstract

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.

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Fig. 1: Blocking LS-AVP signaling eliminates sex differences in extracellular LS-glutamate concentration and in glutamate/GABA ratio of juvenile rats.
Fig. 2: Blocking LS-AVP signaling induces a sex-specific increase in extracellular glutamate, but not GABA, release.
Fig. 3: Sex-specific effects of LS-glutamate signaling on social play behavior in juvenile rats.
Fig. 4: No sex differences in the percentage of Avpr1a+ cells expressing markers for GABAergic neurons or astrocytes in the dorsal LS of juvenile rats.

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Acknowledgements

We would like to thank Jennifer Schiavo, Michelle Verreij, and Nara Nascimento for technical assistance, members of the Veenema lab for input and critically reading the manuscript, Dr. Maurice Manning (Toledo, OH) for kindly providing the V1aR antagonists, and animal caretakers for excellent animal care.

Funding

This research was supported by NARSAD Grant 17382, NSF IOS1253386, and NIH R01MH102456 to AHV.

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  1. Neurobiology of Social Behavior Laboratory, Department of Psychology and Neuroscience Program, Michigan State University, East Lansing, MI, USA

    Remco Bredewold, Catherine Washington & Alexa H. Veenema

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  1. Remco Bredewold
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R.B. and C.W. performed experiments. R.B. and A.V. developed the concept, analyzed the data and wrote the manuscript. A.V. conceived the project and supervised all aspects of the project.

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Correspondence to Alexa H. Veenema.

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Bredewold, R., Washington, C. & Veenema, A.H. Vasopressin regulates social play behavior in sex-specific ways through glutamate modulation in the lateral septum. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01987-z

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