Sensory Neurons From Nf1 Haploinsufficient Mice Exhibit Increased Excitability

1 Departments of Pharmacology and Toxicology, 2 Pediatrics, 3 Microbiology and Immunology, and 4 Neurology, Indiana University School of Medicine, Indianapolis, Indiana Submitted 11 May 2005; accepted in final form 22 July 2005 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. Address for reprint requests and other correspondence: C. M. Hingtgen, Stark Neurosciences Research Institute, Indiana University School of Medicine, 450 W. Walnut St., R2-466, Indianapolis, IN 46202 (E-mail: chingtge{at}iupui.edu )