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Dynamic regulation of excitatory and inhibitory synaptic transmission by growth hormone in the developing mouse brain

Abstract

Normal sensory and cognitive function of the brain relies on its intricate and complex neural network. Synaptogenesis and synaptic plasticity are critical to neural circuit formation and maintenance, which are regulated by coordinated intracellular and extracellular signaling. Growth hormone (GH) is the most abundant anterior pituitary hormone. Its deficiencies could alter brain development and impair learning and memory, while GH replacement therapy in human patients and animal models has been shown to ameliorate cognitive deficits caused by GH deficiency. However, the underlying mechanism remains largely unknown. In this study, we investigated the neuromodulatory function of GH in young (pre-weaning) mice at two developmental time points and in two different brain regions. Neonatal mice were subcutaneously injected with recombinant human growth hormone (rhGH) on postnatal day (P) 14 or 21. Excitatory and inhibitory synaptic transmission was measured using whole-cell recordings in acute cortical slices 2 h after the injection. We showed that injection of rhGH (2 mg/kg) in P14 mice significantly increased the frequency of mEPSCs, but not that of mIPSCs, in both hippocampal CA1 pyramidal neurons and L2/3 pyramidal neurons of the barrel field of the primary somatosensory cortex (S1BF). Injection of rhGH (2 mg/kg) in P21 mice significantly increased the frequency of mEPSCs and mIPSCs in both brain regions. Perfusion of rhGH (1 μM) onto acute brain slices in P14 mice had similar effects. Consistent with the electrophysiological results, the dendritic spine density of CA1 pyramidal neurons and S1BF L2/3 pyramidal neurons increased following in vivo injection of rhGH. Furthermore, NMDA receptors and postsynaptic calcium-dependent signaling contributed to rhGH-dependent regulation of both excitatory and inhibitory synaptic transmission. Together, these results demonstrate that regulation of excitatory and inhibitory synaptic transmission by rhGH occurs in a developmentally dynamic manner, and have important implication for identifying GH treatment strategies without disturbing excitation/inhibition balance.

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Fig. 1: rhGH increases excitatory synaptic transmission and spine density in S1BF L2/3 pyramidal neurons at P14 in vivo and in vitro.
Fig. 2: Pyramidal cells in hippocampal CA1 region show the same mEPSC and mIPSC changes as in S1BF.
Fig. 3: rhGH increases both excitatory and inhibitory synaptic transmission in S1BF at P21.
Fig. 4
Fig. 5: GHR is required for regulation of synaptic transmission by rhGH.
Fig. 6: Regulation of synaptic transmission by rhGH is dependent on NMDA receptors.
Fig. 7: Regulation of E/I ratio by rhGH in S1 L2/3 pyramidal neurons at P14 and P21.

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Acknowledgements

We thank GeneScience Pharmaceuticals and Dr. Mu Sun for providing rhGH. We are grateful to members of the Yu laboratory for suggestions and comments. This work was supported by grants from the National Natural Science Foundation of China (31900702 to GL, 32030049 to XY), the Ministry of Science and Technology of China (2021ZD0202504 to XY), the Key-Area Research and Development Program of Guangdong Province (2019B030335001 to XY), the China Postdoctoral Science Foundation (7113288521 to GYL), and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD). Schematics were created using BioRender.com.

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GYL and XY conceived experiments; GYL performed electrophysiological experiments and data analyses; QZW performed Golgi staining, ELISA and Western blot experiments and data analyses, with help from TJS; GYL and XY wrote the manuscript, QZW, TJS, and XCZ reviewed and edited the manuscript. All authors read and approved the manuscript.

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Correspondence to Guang-ying Li or Xiang Yu.

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Li, Gy., Wu, Qz., Song, Tj. et al. Dynamic regulation of excitatory and inhibitory synaptic transmission by growth hormone in the developing mouse brain. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-01027-w

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  • DOI: https://doi.org/10.1038/s41401-022-01027-w

Keywords

  • growth hormone
  • synaptic transmission
  • synaptic plasticity
  • pyramidal neuron
  • dendritic spine
  • NMDA receptor

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