Background & Aims
The modulation and processing of pain-related signals in the spinal cord constitute a highly complex process coordinated by different cell types. Astrocytes, traditionally viewed as major supportive cells for neurons, play a pivotal role in modulating pain signal processing at the spinal level [1]. Their ability to release neuromodulatory substances positions them as influential regulators of nociception, being capable of impacting synaptic activity of spinal neurons [2,3] and suggest their critical contribution to both attenuation and amplification of pain [3,4]. However, the precise mechanisms governing these neuron-glia interactions remain elusive and warrant thorough investigation. This study aims to elucidate the mechanisms through which astrocytes modulate information processing at spinal synapses and explore the distinctive properties of astrocyte-to-neuron communication within the spinal dorsal horn.
Methods
To analyse the potential involvement of astrocytes, we conducted whole-cell patch-clamp recordings from unidentified dorsal horn neurons with monosynaptic C-fiber input, as well as from identified projection neurons, in acute spinal cord slices from male rats. Additionally, synaptic strength was assessed in vivo by analyzing C-fiber-evoked field potentials in deeply anesthetized rats. GqDREADDs were employed to induce Ca2+ responses in astrocytes upon CNO administration.
Results
We found that GqDREADDs were selectively expressed in astrocytes and functionally effective. Activation with CNO led to robust LTD at nociceptive C-fiber synapses at the spinal cord level, both in vitro and in vivo. This LTD required postsynaptic NMDA receptors and a rise in [Ca2+]i but was independent of postsynaptic G-protein signaling.
Conclusions
Our data challenge the notion that astrocytes predominantly exert enhancing influences on synaptic transmission in the spinal cord. In contrast to the prevailing view, we show that astrocytes effectively depress synaptic transmission at spinal nociceptive synapses. These findings add another level of complexity to the interaction between astrocytes and neurons and show that astrocytes are highly dynamic regulators of the neuronal network at the level of the spinal cord.
References
[1] Lu, HJ., Gao, YJ. Astrocytes in Chronic Pain: Cellular and Molecular Mechanisms. Neurosci. Bull. 39, 425–439 (2023). https://doi.org/10.1007/s12264-022-00961-3
[2] Xanthos, D., Sandkühler, J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci 15, 43–53 (2014). https://doi.org/10.1038/nrn3617
[3] Papouin T, Dunphy J, Tolman M, Foley JC, Haydon PG. Astrocytic control of synaptic function. Philos Trans R Soc Lond B Biol Sci. 2017 Mar 5;372(1715):20160154. doi: 10.1098/rstb.2016.0154. PMID: 28093548; PMCID: PMC5247586.
[4] Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science. 2016 Nov 4;354(6312):572-577. doi: 10.1126/science.aaf8924. PMID: 27811267; PMCID: PMC5488328.
[5] Kronschläger MT, Drdla-Schutting R, Gassner M, Honsek SD, Teuchmann HL, Sandkühler J. Gliogenic LTP spreads widely in nociceptive pathways. Science. 2016 Dec 2;354(6316):1144-1148. doi: 10.1126/science.aah5715. Epub 2016 Nov 10. PMID: 27934764; PMCID: PMC6145441.
Presenting Author
Laura Klinger
Poster Authors
Topics
- Mechanisms: Biological-Molecular and Cell Biology