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<p>Dose-dependent neuromodulation has been well established; however, the molecular mechanisms underlying astrocytic involvement in this process remain largely unexplored. Using the autoregulation of supraoptic oxytocin (OT) neurons (OTNs) as a model, we investigated the role of distinct astrocytic G proteins and their targets in the dose-dependent effects of OT on OTN activity. The results showed that OT in a low concentration (10&#xa0;pmol/L, L-OT) excited OTN activity, whereas a high concentration (1&#xa0;nmol/L, H-OT) inhibited it in brain slices. These effects were abolished upon disruption of astrocytic plasticity using L-aminoadipic acid, a gliotoxin. In primary astrocyte cultures, L-OT slightly reduced the current through astrocyte-specific inwardly rectifying K⁺ channel 4.1 (Kir4.1) while H-OT strongly enhanced it. Selectively blocking Kir4.1 with BaCl₂ (100&#xa0;µmol/L) did not affect the basal activity but blocked the excitatory effect of L-OT in brain slices. In cultured astrocytes, L-OT mobilized Gαq subunit expression, increased glial fibrillary acidic protein (GFAP) filaments, and quickly expanded astrocytic volume, predominantly visible at the somata. Conversely, H-OT released Gαi subunits and induced progressive volume expansion. Pretreatment of brain slices with U73122 (a Gq inhibitor) or SQ22536 (a Gs inhibitor) suppressed L-OT-induced excitation. Conversely, activation of adenylyl cyclase with forskolin reversed the inhibitory effect of H-OT, and inhibition of Gi with pertussis toxin blocked H-OT-induced inhibition. These findings imply that the dose-dependent effects of OT on OTN activity are mediated, at least partially, by different receptor-coupled G proteins and their subsequent modulation of astrocytic Kir4.1 currents, GFAP expression, and volume dynamics. This mechanism underlying the autoregulation of OTN activity provides an important reference for understanding the concentration-dependent neuromodulation.</p>

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G Proteins-Associated Dose-Dependent Effects of Oxytocin on Oxytocin Neuronal Activity and Astrocytic Plasticity of the Supraoptic Nucleus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月22日

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  • Xiao-Yu Liu,
  • Shuo Ling,
  • Yang Liu,
  • Yunhao Jiang,
  • Xiaoran Wang,
  • Shuwei Jia,
  • Chunmei Hou,
  • Yanpeng Li,
  • Delai Qiu,
  • Yu-Feng Wang

摘要

Dose-dependent neuromodulation has been well established; however, the molecular mechanisms underlying astrocytic involvement in this process remain largely unexplored. Using the autoregulation of supraoptic oxytocin (OT) neurons (OTNs) as a model, we investigated the role of distinct astrocytic G proteins and their targets in the dose-dependent effects of OT on OTN activity. The results showed that OT in a low concentration (10 pmol/L, L-OT) excited OTN activity, whereas a high concentration (1 nmol/L, H-OT) inhibited it in brain slices. These effects were abolished upon disruption of astrocytic plasticity using L-aminoadipic acid, a gliotoxin. In primary astrocyte cultures, L-OT slightly reduced the current through astrocyte-specific inwardly rectifying K⁺ channel 4.1 (Kir4.1) while H-OT strongly enhanced it. Selectively blocking Kir4.1 with BaCl₂ (100 µmol/L) did not affect the basal activity but blocked the excitatory effect of L-OT in brain slices. In cultured astrocytes, L-OT mobilized Gαq subunit expression, increased glial fibrillary acidic protein (GFAP) filaments, and quickly expanded astrocytic volume, predominantly visible at the somata. Conversely, H-OT released Gαi subunits and induced progressive volume expansion. Pretreatment of brain slices with U73122 (a Gq inhibitor) or SQ22536 (a Gs inhibitor) suppressed L-OT-induced excitation. Conversely, activation of adenylyl cyclase with forskolin reversed the inhibitory effect of H-OT, and inhibition of Gi with pertussis toxin blocked H-OT-induced inhibition. These findings imply that the dose-dependent effects of OT on OTN activity are mediated, at least partially, by different receptor-coupled G proteins and their subsequent modulation of astrocytic Kir4.1 currents, GFAP expression, and volume dynamics. This mechanism underlying the autoregulation of OTN activity provides an important reference for understanding the concentration-dependent neuromodulation.