Sensory Neurons From Nf1 Haploinsufficient Mice Exhibit Increased Excitability

Department of Microbiology and Immunology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States
Journal of Neurophysiology (Impact Factor: 2.89). 01/2006; 94(6):3670-6. DOI: 10.1152/jn.00489.2005
Source: PubMed


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.

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    • "n the Nf1 + / − mice , but there is little evidence for a strong contribution of synaptic inhibition to the complex extracellular waveform at the level of the mouse MNTB ( Lorteije and Borst , 2011 ) . In both dorsal root ganglion neurons and hippocampal or neocortical interneurons from NF1 mice clear increases in excitability have been observed ( Wang et al . , 2005 ; Omrani et al . , 2015 ) . In the dorsal root ganglion neurons the increased excitability is caused by increased sodium conductance , which depends on the increased Ras activity ( Wang et al . , 2010 ; Duan et al . , 2011 ) . In the interneurons these changes in excitability were caused by a decrease in the hyperpolarization - activated"
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    • "Thus GAPs can be critical proteins in regulating the peripheral sensitization and nociception mediated by Ras signaling cascades. Indeed, we previously demonstrated that primary sensory neurons from mice with reduced expression of neurofibromin, another Ras-GAP, exhibit increased excitability and sensitivity to chemical stimulation (Hingtgen et al. 2006; Wang et al. 2005). "
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    • "The NF1 E4 missense mutant in this respect behaves as a temperature-sensitive hypomorph (Fig. 1C). Of special relevance to the human disease, several haploinsufficient phenotypes have been described in NF1 +/− mammalian cells (Zhu et al. 2002; Wang et al. 2005; Hingtgen et al. 2006). Drosophila NF1 also appears haploinsufficient for growth regulation, since both male and female NF1 E1 /+ or NF1 E2 /+ pupae exhibited a small (∼4%), but highly significant (Student t-test p < 0.0001; n = 45) reduction in length compared with isogenic controls (data not shown). "
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