Abstract
The substantia gelatinosa (SG, lamina II of spinal cord gray matter) is pivotal for modulating nociceptive information from the peripheral to the central nervous system. γ-Aminobutyric acid type B receptors (GABABRs), the metabotropic GABA receptor subtype, are widely expressed in pre- and postsynaptic structures of the SG. Activation of GABABRs by exogenous agonists induces both pre- and postsynaptic inhibition. However, the actions of endogenous GABA via presynaptic GABABRs on glutamatergic synapses, and the postsynaptic GABABRs interaction with glutamate, remain elusive. In the present study, first, using in vitro whole-cell recordings and taking minimal stimulation strategies, we found that in rat spinal cord glutamatergic synapses, blockade of presynaptic GABABRs switched “silent” synapses into active ones and increased the probability of glutamate release onto SG neurons; increasing ambient GABA concentration mimicked GABABRs activation on glutamatergic terminals. Next, using holographic photostimulation to uncage glutamate on postsynaptic SG neurons, we found that postsynaptic GABABRs modified glutamate-induced postsynaptic potentials. Taken together, our data identify that endogenous GABA heterosynaptically constrains glutamate release via persistently activating presynaptic GABABRs; and postsynaptically, GABABRs modulate glutamate responses. The results give new clues for endogenous GABA in modulating the nociception circuit of the spinal dorsal horn and shed fresh light on the postsynaptic interaction of glutamate and GABA.
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Data availability statement
The data that supports the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
The authors thank Prof. Scott M. Thompson, Prof. Cha-Min Tang and Dr. Sunggu Yang (University of Maryland School of Medicine, Baltimore, MD, USA) for support and inspiration; Prof. Eiichi Kumamoto (Saga Medical School, Saga University, Saga, Japan) and Xingwu Yang (University of Pennsylvania School of Engineering and Applied Science Class 2025, Philadelphia, PA, USA) for critical reading of the manuscript. This project was supported by a Jiangsu Province Education Department Grant to K.Y., funds from the Graduate Research and Practice Innovation Program of Jiangsu Province to M.Z. (KYCX20_3088) and Q.C. (KYCX17_1800), and National Natural Science Foundation of China to W.-N.Z. (No. 81671053).
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Funding was provided by National Natural Science Foundation of China (81671053).
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MZ, CS, JD, QC investigation; formal analysis. RM, PJ, W-NZ: formal analysis. KY conceptualization; methodology; investigation; supervision; project administration; resources; writing-original draft; writing-review and editing.
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429_2022_2481_MOESM1_ESM.pptx
Supplementary file1 Supplemental Fig. S1 Normalized uEPSP amplitude to repeat uncaging glutamate. a Example raw uEPSP traces from a representative neuron at different photostimulation times. b Repeat uncaging glutamate (interval 1 min) induces no significant uEPSP amplitude facilitation or depression in 8 min, showing relative amplitudes at each time point compared to the initial values (#1 response). Data are shown as mean ± S.E., n = 5 neurons, one-way ANOVA followed by a Bonferroni post hoc test. P > 0.05 in all groups compared to initial uEPSPs (PPTX 114 KB)
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Zhao, M., Shao, C., Dong, J. et al. GABAB receptors constrain glutamate presynaptic release and postsynaptic actions in substantia gelatinosa of rat spinal cord. Brain Struct Funct 227, 1893–1905 (2022). https://doi.org/10.1007/s00429-022-02481-2
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DOI: https://doi.org/10.1007/s00429-022-02481-2