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Department of Neuroscience, College of Medicine and Brain Institute, University of Florida, Gainesville, Florida 32610
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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We thank K. Foli for technical support and Regeneron Pharmaceuticals for providing NT-3.
This research was supported by National Institute of Neurological Disorders and Stroke Grants NS-15913 (Javits Neuroscience Award) to J. B. Munson and NS-16996 (Javits Neuroscience Award) to L. M. Mendell. Additional support was furnished by NS-14899 and NS-32264 to L. M. Mendall.
Present addresses: R. D. Johnson, Dept. of Physiological Sciences, University of Florida College of Veterinary Medicine, Gainesville, FL 32610; L. M. Mendell, Dept. of Neurobiology and Behaviour, SUNY at Stony Brook, Stony Brook, NY 11794.
When a peripheral nerve is cut, afferent fibers undergo gradual changes in functional properties. Chief among these changes are a decline in afferent conduction velocity and in the amplitude of the excitatory postsynaptic potentials (EPSPs) they elicit in intact motoneurons (Goldring et al. 1980 These data were obtained from 13 adult female cats. Eight of these cats were normal unoperated controls from which data have been published previously (Mendell et al. 1995
Monosynaptic EPSPs produced in LGS motoneurons by stimulation of MG afferents that were either axotomized or axotomized-and-saline-treated for 4-5 wk averaged 1.0 mV (Table 1). This result represents a decline of 50% from the mean 2.0 mV EPSPs produced by intact MG afferents in intact LGS motoneurons (Mendell et al. 1995
The amplitude of EPSPs elicited by axotomized afferents in intact motoneurons (Goldring et al. 1980
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
; Mendell et al. 1995). These changes have been suggested to reflect the loss of trophic factor(s) normally supplied by the periphery (reviewed in Titmus and Faber 1990). Support for this suggestion comes from the fact that axotomized afferents recover after regeneration into either muscle or skin (Johnson et al. 1995; Mendell et al. 1995), either of which might be a source of trophic factors such as neurotrophin-3 (NT-3) (Schechterson and Bothwell 1991).
). During development NT-3 is required for survival of large diameter muscle afferents (Hory-Lee et al. 1993) that are absent in animals lacking NT-3 (Ernfors et al. 1994). NT-3 mRNA is expressed in muscle spindles (Copray and Brouwer 1994).
) and in experimental peripheral neuropathy (Gao et al. 1995). These associations between NT-3 and development and function of spindle afferent fibers have prompted us to test the effects of applying NT-3 to the cut end of axotomized muscle afferents on the synaptic potentials that they produce in intact motoneurons.
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
). In the other five cats (one of these cats also from Mendell et al. 1995; see Table 1) the medial gastrocnemius (MG) nerve was severed in the popliteal fossa, and the MG muscle was excised to prevent self-regeneration. In the cat from the Mendell study, the axotomized nerve was capped with Gore-Tex; in the other four the nerve end was coupled by a Gore-Tex sleeve to a silastic tube and mini-osmotic pump that provided either 0.9% saline (2 cats) or NT-3 at 60 µg/day (2 cats). Acute terminal experiments were performed 4-5 wk after initial surgery.
View this table:
TABLE 1.
Properties of EPSPs generated by normal, axotomized, and 
-NT-3-treated axotomized MG afferents and
of their untreated target LGS motoneurons
; Foehring et al. 1986). Conduction time, input resistance, rheobase, and afterhyperpolarization half-decay time (AHP) were determined for antidromically identified, intracellularly recorded lateral gastrocnemius/soleus (LGS) motoneurons with action potential amplitude >60 mV. EPSPs (at 0.5 and 18 Hz and with bursts of 32 shocks at 167 Hz every 2 s, averaged in register) were generated in LGS motoneurons by stimulation of the MG nerve at ~3 times threshold. EPSP modulation during the burst {100[(EPSP30 + EPSP31)/2]/[EPSP1]}% expressed the percent increase (positive modulation) or decrease (negative modulation) in amplitude from the first EPSP in the burst to the mean of EPSPs 30 and 31 (Collins et al. 1984).
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
). When the cut afferents were treated with NT-3 throughout their 5-wk period of axotomy, EPSP amplitude increased to well in excess of normal values, reaching a mean amplitude of 5.0 mV. The very largest EPSPs (>8 mV) were seen in both NT-3-treated cats but not in the eight normal or the three axotomized/untreated cats (Fig. 1). Figure 1 shows that another effect of NT-3 was to reduce substantially the fraction of EPSPs with amplitude <1 mV. Despite the very large change in EPSP amplitude induced by NT-3, no alteration was observed in EPSP amplitude modulation during high-frequency stimulation (about 
45% in both cases; see Table 1). No differences in properties of the untreated target LGS motoneurons were observed, suggesting that motoneuron sampling or altered motoneuron properties did not account for the changes in EPSP amplitude (Table 1).
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FIG. 1.
Cumulative sum histograms of amplitudes of excitatory postsynaptic currents (EPSPs) generated in lateral gastrocnemius/soleus (LGS) motoneurons by normal, axotomized-and-saline-treated and axotomized-and-neurotrophin-3 (NT-3)-treated medial gastrocnemius (MG) group Ia afferents. Amplitudes are reduced by axotomy but are made supernormal by NT-3 treatment. Inset: largest EPSPs from each sample. From largest to smallest, EPSPs were generated by NT-3-treated, normal, and axotomized/untreated MG afferents, respectively. Note prolonged latency of EPSP generated by axotomized/untreated afferents and normal latency of EPSP elicited by NT-3-treated MG afferents, indicating effect of NT-3 on conduction velocity of group Ia afferents. Calibrations: 1 mV, 1 ms.
) or those furnished with saline through the cut end exhibited a substantial decrease in conduction velocity. This reduction was evident in the increased latency of the EPSPs generated by the axotomized/untreated afferents (Fig. 1, inset) and the afferent volley of the cord dorsum potential, which averaged 128% of normal latency (not shown). When the damaged afferents were treated with NT-3 an apparently complete recovery in conduction velocity was observed (Fig. 1, inset and cord dorsum afferent volley) (cf. Munson et al. 1997).
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
; Mendell et al. 1995) and the conduction velocity of axotomized afferents (Collins et al. 1986) are known to decline as a result of the axotomy. Evidence that such changes could reflect the loss of substances normally retrogradely carried from the periphery was obtained for motoneurons (Czeh et al. 1978) and for sympathetic postganglionic fibers treated with blockers of axonal transport (Purves 1976). The present data indicate that exogenous NT-3 applied to axotomized group Ia muscle afferents not only reverses the axotomy-induced decline of conduction velocity but also results in the generating of supernormal EPSPs. This result is consistent with the fact that the trkC receptor that binds NT-3 is found on group I afferents (McMahon et al. 1994). The restored conduction velocity may be due to restoration of axon caliber, resulting from up-regulation of neurofilament production, as shown for nerve growth factor (NGF)-sensitive afferents (Verge et al. 1990).
) modulation values become less negative (less abnormal) as EPSP amplitude increases toward normal values. A simple explanation is that NT-3 administration at these levels was much more potent than the peripheral tissue in inducing recovery of the Ia synapse. Transmitter release increased so much (accounting for the very large EPSPs) that the connections remained susceptible to depression in accordance with the normally greater susceptibility of the largest EPSPs to depress during high-frequency stimulation (Collins et al. 1984; Mendell et al. 1995). A second possibility is that the recovery process involved sprouting of terminals of NT-3-treated afferents, with each release site functioning in the same manner as those of untreated axotomized afferents. At the very least we cannot equate the periphery-mediated recovery with the neurotrophin-induced recovery, although these two modes might share certain features.
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FOOTNOTES |
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Address for reprint requests: J. B. Munson, Box 100244, JHMHSC, Gainesville, FL 32610-0244.
Received 24 October 1996; accepted in final form 10 January 1997.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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-motoneurons as revealed by high frequency stimulation of Ia afferent fibers.
J. Neurophysiol.
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