Deletion of GABA-B Receptor in Schwann Cells Regulates Remak Bundles and Small Nociceptive C-fibers

• Published in: Glia 2014-04, Vol.62 (4), p.548-565
• Main Authors: Faroni, Alessandro, Castelnovo, Luca Franco, Procacci, Patrizia, Caffino, Lucia, Fumagalli, Fabio, Melfi, Simona, Gambarotta, Giovanna, Bettler, Bernhard, Wrabetz, Lawrence, Magnaghi, Valerio
• Format: Article
• Language: English
• Subjects: Animals; C-fibers; calcitonin gene related protein; Calcitonin Gene-Related Peptide - metabolism; Cells, Cultured; Differentiation; dorsal root ganglion; Gait - genetics; Ganglia, Spinal - cytology; Genotype & phenotype; Hyperalgesia - pathology; Leprosy; Male; Medical research; Mice; Mice, Transgenic; Microscopy, Confocal; Microscopy, Electron; Myelin P0 Protein - genetics; Nerve Fibers, Unmyelinated - physiology; Neuregulin-1 - metabolism; Neurons - physiology; nociception; non-myelinating Schwann cell; Pain Threshold - physiology; Receptors, GABA-B - deficiency; Receptors, GABA-B - genetics; Schwann Cells - physiology; Schwann Cells - ultrastructure; sciatic nerve; Sciatic Nerve - cytology
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22625

The mechanisms regulating the differentiation into non‐myelinating Schwann cells is not completely understood. Recent evidence indicates that GABA‐B receptors may regulate myelination and nociception in the peripheral nervous system. GABA‐B receptor total knock‐out mice exhibit morphological and molecular changes in peripheral myelin. The number of small myelinated fibers is higher and associated with altered pain sensitivity. Herein, we analyzed whether these changes may be produced by a specific deletion of GABA‐B receptors in Schwann cells. The conditional mice (P0‐GABA‐B1fl/fl) show a morphological phenotype characterized by a peculiar increase in the number of small unmyelinated fibers and Remak bundles, including nociceptive C‐fibers. The P0‐GABA‐B1fl/fl mice are hyperalgesic and allodynic. In these mice, the morphological and behavioral changes are associated with a downregulation of neuregulin 1 expression in nerves. Our findings suggest that the altered pain sensitivity derives from a Schwann cell‐specific loss of GABA‐B receptor functions, pointing to a role for GABA‐B receptors in the regulation of Schwann cell maturation towards the non‐myelinating phenotype. GLIA 2014;62:548–565 Main Points Metabotropic GABA‐B receptors exert physiologic effects in PNS GABA‐B‐related changes are Schwann cell‐autonomous and non‐autonomous GABA‐B have a role in the Schwann cells maturation towards the non‐myelinating phenotype