Sensory neurons from Nf1 haploinsufficient mice exhibit increased excitability.
Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by tumor formation. People with NF1 also can experience more intense painful responses to stimuli, such as minor trauma, than normal. NF1 results from a heterozygous mutation of the NF1 gene, leading to decreased levels of neurofibromin, the protein product of the NF1 gene. Neurofibromin is a guanosine triphosphatase activating protein (GAP) for Ras and accelerates the conversion of active Ras-GTP to inactive Ras-GDP; therefore mutation of the NF1 gene frequently results in an increase in activity of the Ras transduction cascade. Using patch-clamp electrophysiological techniques, we examined the excitability of capsaicin-sensitive sensory neurons isolated from the dorsal root ganglia of adult mice with a heterozygous mutation of the Nf1 gene (Nf1+/-), analogous to the human mutation, in comparison to wildtype sensory neurons. Sensory neurons from adult Nf1+/- mice generated a more than twofold higher number of action potentials in response to a ramp of depolarizing current as wild-type neurons. Consistent with the greater number of action potentials, Nf1+/- neurons had lower firing thresholds, lower rheobase currents, and shorter firing latencies than wild-type neurons. Interestingly, nerve growth factor augmented the excitability of wild-type neurons in a concentration-related manner but did not further alter the excitability of the Nf1+/- sensory neurons. These data clearly suggest that GAPs, such as neurofibromin, can play a key role in the excitability of nociceptive sensory neurons. This increased excitability may explain the painful conditions experienced by people with NF1.
Wang
Yue
Y
Departments of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, 46202, USA.
Nicol
G D
GD
Clapp
D Wade
DW
Hingtgen
Cynthia M
CM
D000200:Action Potentials / Q000235:genetics* / Q000502:physiology / Q000528:radiation effects; D000704:Analysis of Variance; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D005727:Ganglia, Spinal / Q000166:cytology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D020932:Nerve Growth Factor / Q000494:pharmacology; D009456:Neurofibromatosis 1 / Q000235:genetics*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects
D020932:Nerve Growth Factor; D002211:Capsaicin