Deletion of GABA-B receptor in Schwann cells regulates remak bundles and small nociceptive C-fibers.
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-B1(fl/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-B1(fl/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.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy; Blond McIndoe Laboratories, The University of Manchester, Institute of Inflammation and Repair, M13 9PT, Manchester, United Kingdom.
Alessandro
A
Faroni
Luca Franco
LF
Castelnovo
Patrizia
P
Procacci
Lucia
L
Caffino
Fabio
F
Fumagalli
Simona
S
Melfi
Giovanna
G
Gambarotta
Bernhard
B
Bettler
Lawrence
L
Wrabetz
Valerio
V
Magnaghi
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002478:Cells, Cultured; D005684:Gait / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D018993:Myelin P0 Protein / Q000235:genetics; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology*; D020890:Neuregulin-1 / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D017288:Pain Threshold / Q000502:physiology*; D018080:Receptors, GABA-B / Q000172:deficiency* / Q000235:genetics; D012583:Schwann Cells / Q000502:physiology* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000166:cytology
D018993:Myelin P0 Protein; D020890:Neuregulin-1; D018080:Receptors, GABA-B; D015740:Calcitonin Gene-Related Peptide
C-fibers; calcitonin gene related protein; dorsal root ganglion; nociception; non-myelinating Schwann cell; sciatic nerve