The low-affinity neurotrophin receptor p75 regulates the function but not the selective survival of specific subpopulations of sensory neurons - PubMed (original) (raw)

The low-affinity neurotrophin receptor p75 regulates the function but not the selective survival of specific subpopulations of sensory neurons

C L Stucky et al. J Neurosci. 1997.

Abstract

Mice with a targeted deletion of the low-affinity neurotrophin receptor p75 (p75-/-) exhibit a 50% loss of large- and small-diameter sensory neurons in the dorsal root ganglion. Using neurophysiological recording techniques, we now show that p75 is not required for the survival of specific, functionally defined subpopulations of sensory neurons. Rather, p75-/- mice exhibit losses of neurons that subserve nociceptive as well as non-nociceptive functions. The receptive properties of large myelinated afferent fibers were normal in p75-/- mice. However, the receptive properties of subpopulations of afferent fibers with thin myelinated or unmyelinated axons were strikingly impaired in mice lacking p75. Furthermore, the presence of p75 is required for normal mechanotransduction in C fibers and D-hair receptors and normal heat sensitivity in A-fiber nociceptors.

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Figures

Fig. 1.

Fig. 1.

A, _In vitro_skin-nerve preparation. B, Electrical stimulation procedure used to “mark” C fibers. C fibers have a stable latency after supramaximal electrical stimulation (3 sec interstimulus interval) of the receptive field (traces 1–2). However, after adequate activation of the fiber with a mechanical stimulus (trace 3, mech. stim.), there is a typical shift in the latency of the electrically evoked response that recovers gradually (traces 4–7). The shift in latency and recovery indicates that both the electrically and the mechanically evoked action potentials were evoked from the same unit.

Fig. 2.

Fig. 2.

Representative examples of response properties of cutaneous afferent fibers. A, Among the Aβ fibers, SA mechanoreceptors fire tonically throughout a constant low-intensity force stimulus, whereas RA fibers fire only at the on- and offset of the stimulus. Histograms (bin width = 1 sec) indicate impulses/sec during a sustained mechanical stimulus.B, Among Aδ fibers, A-fiber nociceptors require high-intensity mechanical stimuli for activation and fire tonically throughout the stimulus. In contrast, D-hair receptors have very low thresholds for activation (<1.0 mN) and fire at high frequencies at the on- and offset of the stimulus. C, Representative examples of responses of a C fiber to mechanical, heat, and cold stimuli are illustrated. Response is plotted as instantaneous frequency, where each dot represents one action potential.

Fig. 3.

Fig. 3.

Prevalence of functionally defined sensory receptors among Aβ and Aδ fibers. The _asterisk_indicates that the number of fibers in p75−/− mice is significantly different from that for p75+/+ mice; p < 0.05, χ2 test.

Fig. 4.

Fig. 4.

Stimulus–response functions of cutaneous fibers to constant force stimuli. There were no statistically significant differences in the mechanical stimulus–response functions of SA (F(1,139) = 0.44, p > 0.5), RA (F(1,158) = 2.24,p > 0.1), or AM (F(1,458) = 2.41, p > 0.1) fibers between p75−/− and p75+/+ mice. However, the stimulus–response functions for D-hair receptors (F(1,208) = 30, p < 0.001) and C fibers (F(1,277) = 16.5,p < 0.001) were significantly reduced in p75−/− mice, compared with p75+/+ mice. Values indicate mean frequency ± SEM of action potentials per second for all fibers. Statistical differences were tested using ANOVA.

Fig. 5.

Fig. 5.

Mean discharge frequency per second during supramaximal mechanical stimuli for C fibers and D-hair receptors.A, C fibers in p75−/− mice exhibited reduced frequency of firing throughout a supramaximal stimulus, compared with p75+/+ mice. Bars (bin width = 1 sec) indicate the mean impulses/sec evoked in response to a 200 mN sustained stimulus for all C fibers tested. B, D-hair receptors in p75−/− mice exhibited reduced frequency of firing, primarily during the first 2 sec after onset of the stimulus. Bars indicate the mean impulses/sec evoked in response to a 100 mN sustained stimulus for all D-hair receptors tested.

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