Peripheral gating of mechanosensation by glial diazepam binding inhibitor
Xinmeng Li, Arthur Silveira Prudente, Vincenzo Prato, Xianchuan Guo, Han Hao, Frederick Jones, Sofia Figoli, Pierce Mullen, Yujin Wang, Raquel Tonello, Sang Hoon Lee, Shihab Shah, Benito Maffei, Temugin Berta, Xiaona Du, Nikita Gamper
Xinmeng Li, Arthur Silveira Prudente, Vincenzo Prato, Xianchuan Guo, Han Hao, Frederick Jones, Sofia Figoli, Pierce Mullen, Yujin Wang, Raquel Tonello, Sang Hoon Lee, Shihab Shah, Benito Maffei, Temugin Berta, Xiaona Du, Nikita Gamper
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Research Article Neuroscience

Peripheral gating of mechanosensation by glial diazepam binding inhibitor

Abstract

We report that diazepam binding inhibitor (DBI) is a glial messenger mediating crosstalk between satellite glial cells (SGCs) and sensory neurons in the dorsal root ganglion (DRG). DBI is highly expressed in SGCs of mice, rats, and humans, but not in sensory neurons or most other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without major effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as an unconventional agonist and positive allosteric modulator at the neuronal GABAA receptors, particularly strongly affecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons, and these are also more enwrapped with DBI-expressing glia, as compared with other DRG neurons, suggesting a mechanism for a specific effect of DBI on mechanosensation. These findings identified a communication mechanism between peripheral neurons and SGCs. This communication modulates pain signaling and can be targeted therapeutically.

Authors

Xinmeng Li, Arthur Silveira Prudente, Vincenzo Prato, Xianchuan Guo, Han Hao, Frederick Jones, Sofia Figoli, Pierce Mullen, Yujin Wang, Raquel Tonello, Sang Hoon Lee, Shihab Shah, Benito Maffei, Temugin Berta, Xiaona Du, Nikita Gamper

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Figure 8

Mechanosensitive neurons are specifically coupled to DBI-expressing glia.

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Mechanosensitive neurons are specifically coupled to DBI-expressing glia...
(A) Heatmap for expression of DBI, Gabra1, Gabrg2, Piezo2, and TRPV1 in different populations of mouse DRG neurons and glia; data from ref. 53. (B–D) FISH analysis of Gabra1, Gabrg2, and Piezo2 mRNA expression in mouse DRG. Example stainings are shown in B. Scale bars: 50 μm. Proportions of Gabra1+ and Gabrg2+ neurons that were also positive for Piezo2 are analyzed in C; proportions of Piezo2+ neurons that were also positive for either Gabra1 or Gabrg2 are analyzed in D. (E–G) Colocalization of γ2 GABAA and DBI immunofluorescence in rat DRG. Example stainings are shown in E. Scale bars: 50 μm. (F) Cell bodies of the γ2-positive DRG neurons were auto-detected with Cellpose, and the automatically detected segments were radially dilated by 10 and shrunk by 3 pixels. DBI immunofluorescence was analyzed in the “doughnut” space between the contracted and dilated segments (schematized in the inset; see Methods). Plots show correlation between the somatic γ2 mean fluorescence and “doughnut” DBI mean fluorescence. (G) Correlation between the somatic diameter of the DRG neurons and DBI integrated density. (H and I) DBI immunofluorescence and FISH analysis of Trpv1 and Piezo2 mRNA expression in mouse DRG. Example stainings are shown in H. Scale bars: 50 μm. In I, a similar approach to that shown in F is shown: cell bodies of Trpv1+ or Piezo2+ neurons were auto-detected, and the DBI immunofluorescence in the dilated segments was measured (see Methods) and compared between the Trpv1+ and Piezo2+ neurons. Data from each biological replicate are color-coded; means from each replicate are shown in large symbols. P = 0.077 is for comparison of means per replicate; P = 0.005 is for comparison of means of individual values (unpaired t test).