Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, New York 11794-5230
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ABSTRACT |
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Arvanov, Viktor L.,
Bradley S. Seebach, and
Lorne M. Mendell.
NT-3 Evokes an LTP-Like Facilitation of AMPA/Kainate
Receptor-Mediated Synaptic Transmission in the Neonatal Rat Spinal
Cord.
J. Neurophysiol. 84: 752-758, 2000.
Neurotrophin-3 (NT-3) is a neurotrophic factor required
for survival of muscle spindle afferents during prenatal development. It also acts postsynaptically to enhance the monosynaptic excitatory postsynaptic potential (EPSP) produced by these fibers in motoneurons when applied over a period of weeks to the axotomized muscle nerve in
adult cats. Similar increases in the amplitude of the monosynaptic EPSP
in motoneurons are observed after periodic systemic treatment of
neonatal rats with NT-3. Here we show an acute action of
NT-3 in enhancing the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA/kainate) receptor-mediated fast monosynaptic EPSP elicited in motoneurons by dorsal root (DR) stimulation in the in vitro hemisected neonatal rat spinal cord. The receptor tyrosine kinase inhibitor K252a blocks this action of NT-3 as does the calcium chelator
bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic
acid (BAPTA) injected into the motoneuron. The effect of NT-3 resembles
long-term potentiation (LTP) in that transient bath application of NT-3 to the isolated spinal cord produces a long-lasting increase in the
amplitude of the monosynaptic EPSP. An additional similarity is that
activation of N-methyl-D-aspartate (NMDA)
receptors is required to initiate this increase but not to maintain it.
The NMDA receptor blocker MK-801, introduced into the motoneuron
through the recording microelectrode, blocks the effect of NT-3,
indicating that NMDA receptors in the motoneuron membrane are crucial.
The effect of NT-3 on motoneuron NMDA receptors is demonstrated by its
enhancement of the depolarizing response of the motoneuron to
bath-applied NMDA in the presence of tetrodotoxin (TTX). The potentiating effects of NT-3 do not persist beyond the first postnatal week. In addition, EPSPs with similar properties evoked in the same
motoneurons by stimulation of descending fibers in the ventrolateral funiculus (VLF) are not modifiable by NT-3 even in the initial postnatal week. Thus, NT-3 produces synapse-specific and age-dependent LTP-like enhancement of AMPA/kainate receptor-mediated synaptic transmission in the spinal cord, and this action requires the availability of functional NMDA receptors in the motoneuron.
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INTRODUCTION |
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Neurotrophin-3
(NT-3) is well established as a trophic factor for group Ia axons
supplying muscle spindles (Chen and Frank 1999).
Prenatally it acts as a "survival" factor for group I spindle afferents in rats (Zhou et al. 1998
), although this
effect is transient and restricted to early developmental stages
(Horton et al. 1998
). In the adult cat, chronic
application of NT-3 to the proximal cut end of a muscle nerve reverses
the decline in conduction velocity and central synaptic drive of
axotomized group Ia fibers (Mendell et al. 1999
;
Munson et al. 1997
). Additionally, in the first
postnatal week when the strength of synaptic inputs from dorsal root
(DR) to motoneurons is increasing (Seebach and Mendell
1996
), systemic treatment of rats with NT-3 results in larger
than normal fast excitatory postsynaptic potentials (EPSPs) evoked by
dorsal root stimulation (DR-EPSPs) (Seebach et al.
1999
). Furthermore, there is some indication that endogenous
NT-3 acts tonically over this period to promote development of this
synaptic connection (Seebach et al. 1999
). Since the
blood brain barrier is not well developed in these young rats
(Tonra and Mendell 1997
), and in view of the acute
effects of NT-3 at central synapses (Kang and Schuman
1995
; Stoop and Poo 1996
), a direct action of
NT-3 on the spindle afferent connection to motoneurons is a possible explanation for these findings during early postnatal development. This
has prompted an investigation of the acute action of NT-3 on EPSPs
produced in neonatal rat motoneurons.
DR-EPSPs in neonatal rat motoneurons are mediated by activation of
N-methyl-D-aspartate (NMDA) and non-NMDA
glutamate receptors. An early, fast, likely monosynaptic component is
mediated by non-NMDA -amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA)/kainate receptors and blocked by the AMPA/kainate receptor
blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (Pinco and
Lev-Tov 1993
). The NMDA receptor that is selectively inhibited
by the competitive antagonist 2-amino-5-phosphonovaleric acid (APV)
(Davies et al. 1981
) and the noncompetitive antagonist MK-801 (Davies et al. 1988
) contributes mainly to
generating a slower component of EPSP that is likely at least partly
polysynaptic. Activation of NMDA receptors depends on membrane
potential because of the Mg2+ block (Ault
et al. 1980
; Nowak et al. 1984
) that is reduced
with depolarization. These components exhibit changes during perinatal development (Jiang et al. 1990
; Pinco and Lev Tov
1993
; Ziskind-Conhaim 1990
) with transmission
being restricted initially to NMDA receptor (NMDAR)-mediated slow
EPSPs. In the postnatal period, fast EPSPs mediated by AMPA/kainate
receptors become evident and within 1-2 wk after birth the
NMDAR-mediated component disappears. Another AMPA/kainate
receptor-mediated synaptic projection onto mammalian spinal
motoneurons from axons of the ventrolateral funiculus (VLF) becomes
functional about 1 wk earlier (Pinco and Lev-Tov 1994
).
Here we compared the effect of NT-3 on intracellularly recorded EPSPs evoked by electrical stimulation of DR and VLF in antidromically identified motoneurons in the hemisected spinal cord from animals of two age groups, "postnatal" 1- to 7- and 8- to 15-day old rats. We provide evidence that during the first postnatal week a brief exposure to NT-3 acutely increases the amplitude of the "fast" AMPA/kainate receptor-mediated DR-evoked fast EPSP, a potentiation that persists well beyond removal of NT-3. Motoneuron NMDA receptors are required to initiate the NT-3-induced EPSP increase but not to maintain it. This action is synapse specific in that it does not affect fast AMPA/kainate receptor-mediated EPSPs produced by VLF axons. It is also age specific in that it cannot be elicited in either pathway after the first week. We demonstrate that this action of NT-3 resembles LTP and speculate that this effect may play an important role in the development of the Ia/motoneuron connection in the neonatal rat.
Portions of these results have been reported previously in abstract
form (Arvanov et al. 1999a; Mendell and Arvanov
1999
).
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METHODS |
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Intracellular recordings were obtained from antidromically
identified lumbar spinal motoneurons in the L5 segment in 121 spinal cord preparations isolated from neonatal male Sprague-Dawley rats 1-15
days old. The general experimental methods have been described previously (Fulton and Walton 1986; Seebach and
Mendell 1996
; Seebach et al. 1999
). Rats were
anesthetized in ether, or in the case of 1- and 2-day-old rats, by
placing them on ice, and killed by decapitation. After laminectomy from
the ventral surface, the lumbar region of the spinal cord was removed.
It was hemisected in a dissection chamber superfused with cold (10°C)
artificial cerebrospinal fluid (ACSF) containing as follows (in mM):
117 NaCl, 4.7 KCl, 2.5 CaCl2, 2.0 MgSO4, 25 NaHCO3, 1.2 NaH2PO4, 11 dextrose,
aerated with 95% O2-5%
CO2 (pH 7.4). These Mg2+
and Ca2+ concentrations were chosen to eliminate
the discharge of motoneurons in response to stimulation of the entire
L5 dorsal root. The medial surface of the left hemicord was pinned to a
Sylgard-coated surface in a recording chamber that was continuously
perfused at 10 ml/min with aerated ACSF at 30°C. The VLF was
dissected free of the spinal cord at T12 by the use of sharpened
tungsten microneedles, as previously described (Pinco and
Lev-Tov 1994
). Suction stimulating electrodes with
silver-silver chloride internal wires were attached to the L5 ventral
root, to peeled, cut VLF axon bundles, and to the cut L5 dorsal root
(Fig. 1). To minimize generation of
action potentials evoked by the VLF, it was necessary to use VLF axon bundles of
100 µm in diameter.
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Intracellular recordings (microelectrodes 70-110 M were filled with
3 M potassium acetate) were made from motoneurons identified by
antidromic response to ventral root stimulation. Electrical stimuli of
60-µs duration were delivered separately to the DR and VLF to
synaptically activate the motoneuron. The intensity (80-200 µA) was
chosen to be just supramaximal for evoking the maximum monosynaptic
fast EPSP, the location of whose peak was determined as described
previously (Seebach and Mendell 1996
). The responses to
10 stimuli were averaged (pClamp 8, Axon Instruments). A stimulation
rate of 0.05-0.1 Hz was chosen to prevent frequency-dependent changes
in successive responses either in controls or after NT-3 administration. This protocol was delivered every 5 min in control periods and during/after NT-3 or drug administration. Each spinal cord
was used for only a single NT-3 application. Motoneuron input resistance and rheobase were estimated by passing current pulses (100 ms) through the intracellular recording electrode as described previously (Fulton and Walton 1986
; Seebach and
Mendell 1996
).
Unless otherwise stated, drugs were added to the perfusion solution.
NT-3 was administered at a concentration of 0.2 µg/ml, except as
noted. The change in the peak amplitude of the monosynaptic fast EPSP
after NT-3 or other treatments was calculated using the following
formula: % change in EPSP = [(100 × EPSP2/EPSP1) 100].
The results are presented as mean ± SE. Unless otherwise mentioned, a paired two-sided t-test was used to evaluate
the statistical significance of the observed changes; in these cases the response of the same cell was compared before and after drug application. Because multiple such tests were carried out, it is
necessary to use a more conservative value of P for judging statistical significance. Using the Bonferroni correction, we established a value of P = 0.004 for study-wide
statistical significance at the 0.05 level.
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RESULTS |
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Administration of NT-3 (0.2 µg/ml) to spinal cords removed from
rats during the first postnatal week resulted in facilitation of the
monosynaptic fast component of DR-EPSPs beginning 10-15 min after
application and lasting at least 3 h after washout of NT-3 (Fig.
2, A and C; also
see Fig. 5C). This fast
component is mediated by CNQX-sensitive AMPA/kainate receptors (Fig.
4A) (Thomas et al.
1998). Figures 2A and
5A also suggest that NT-3 leads to potentiation of a late polysynaptic response. This could not
be evaluated quantitatively because of the contribution of the falling
phase of the monosynaptic EPSP to the later components of the response.
NT-3 produced no significant effect on the CNQX-sensitive VLF-EPSPs
(
8.5% ± 3.7, n = 18; P = 0.16)
recorded in the same motoneurons indicating that the DR-evoked changes
were not due to generalized changes in motoneuron properties (Fig. 2,
B and C). The mean maximum facilitation of the
fast component of DR-EPSPs averaged over all motoneurons studied was
48.2 ± 9.5% (n = 29, P < 0.00007). Although dose-response effects were not investigated systematically, in five preparations NT-3 produced a similar
potentiation at a lower concentration (0.1 µg/ml, Fig.
1A), while at 0.01 µg/ml, it was without effect
(n = 4). Treatment with NT-3 produced no significant
action on the resting membrane potential (
68.7 ± 1 mV in
control versus
69.6 ± 1 mV in NT-3, n = 29, P = 0.17) or input resistance (31 ± 2.5 M
in
control versus 27 ± 3 M
in NT-3, n = 29, P = 0.12) of the motoneurons. Treatment with other neurotrophins [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-4/5 (NT-4/5)] at similar doses did not elicit these synaptic effects (not illustrated).
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The facilitatory action of NT-3 on the DR-EPSP was prevented by
pretreatment with K-252a (200 nM) (P = 0.32;
n = 6; Fig. 3, A and C; Fig.
6), an inhibitor of receptor tyrosine
kinases (Knusel and Hefti 1992), suggesting the
involvement of the trk family of receptor tyrosine kinases.
Administration of K-252a alone did not significantly alter the fast
component of DR-EPSPs (0.80 ± 0.98%; n = 6;
P = 0.74). The NT-3 effects probably involve increased intracellular calcium since allowing
bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) to diffuse into the motoneuron from the recording microelectrode (Lancaster and Nicoll 1987
) prevented
NT-3 from potentiating the fast EPSP (P = 0.31;
n = 5; Figs. 3B and 6).
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Interestingly, the facilitatory action of NT-3 on DR-EPSPs was greater
in the motoneurons with resting membrane potential of 60 to
66 mV
than in more hyperpolarized ones (not illustrated). This effect was not
correlated with EPSP amplitude itself (not illustrated). However, as
displayed in Fig. 3C, we observed that the effect of NT-3
was greater in cells in which the membrane potential at the peak of the
monosynaptic EPSP was more positive. We tested the significance of this
difference by dividing the data into two groups according to the median
value of membrane potential at EPSP amplitude peak (i.e., median split
along the abscissa). The potentiating effect of NT-3 was significantly
greater in motoneurons where membrane potential at EPSP peak was more positive than
63 mV (86.3 ± 11.8%; n = 15) than in those in which it was more negative (9.2 ± 3.9%; n = 14) (P < 0.00004; 2-sided t-test with unequal variance; df = 27). Since the NMDA
receptor is known to function in a voltage-dependent manner so that it is more active at a more depolarized membrane potential (see
INTRODUCTION), this finding suggested a possible role for
the NMDA receptor in mediating the NT-3 induced effect.
NT-3 did not produce a significant action on DR-EPSPs in motoneurons
taken from animals older than 1 wk even when tested on motoneurons with
membrane potential at the peak of the monosynaptic fast EPSP between
52 and
63 mV (8-15-day-old rats; P = 0.37, n = 8; Fig. 6). This is consistent with a role for the
NMDA receptor in the NT-3 induced effect since the contribution of NMDA
receptors to the DR-EPSPs decreases during the first postnatal week
(see INTRODUCTION; Jiang et al. 1990
;
Pinco and Lev-Tov 1993
; Ziskind-Conhaim 1990
).
The effect of the NMDA-receptor antagonist d-APV on NT-3
induced potentiation of the DR EPSP was tested on motoneurons with membrane potential at the peak of the fast EPSP in the range of 52 to
63 mV (i.e., normally sensitive to NT-3) in animals younger than 1 wk. Addition of 40 µM d-APV alone to the bath produced a small
decrease in the peak amplitude of the fast DR-EPSP averaging about
10%, but markedly shortened its decay, indicating a greater effect on
later components of the response (Ziskind-Conhaim 1990
; Fig. 4A). APV had no effect on the VLF-EPSP in the same
cell (Fig. 4A). Addition of NT-3 to d-APV-treated
preparations resulted in no change in the fast component of the
DR-EPSP (P = 0.44; n = 6; Figs.
4A and 6), indicating a role for NMDA receptors in the development of NT-3 induced potentiation of the EPSP. Addition of CNQX
to the bath eliminated most of the surviving response, indicating that
it was mediated by AMPA/kainate receptors. The small remaining
depolarizing response was not present in experiments where bicuculline
and strychnine were also added (not illustrated; see also Pinco
and Lev Tov 1993
), indicating that it was a depolarizing inhibitory response.
To examine the possibility that motoneuron NMDA receptors are necessary
for the NT-3-induced effect, we applied the NMDA antagonist MK-801
intracellularly by allowing it to leak from the recording microelectrode. This restricted blockade of NMDA receptors to those in
the recorded motoneuron (Arvanov et al. 1999b;
Berretta and Jones 1996
). In control experiments,
motoneuron depolarization produced by bath-applied NMDA but not that
produced by AMPA was blocked by this procedure (not illustrated).
Within 20-45 min of impalement, the amplitude of the DR-evoked slow
EPSP diminished substantially with only a small effect on the fast
DR-EPSP and almost no action on VLF-EPSPs in the same motoneuron (Fig.
4B), i.e., similar to the effect of d-APV. Under these
conditions (membrane potential of
53 to
63 mV at monosynaptic EPSP
peak), NT-3 had no significant effect on the fast DR EPSP in animals
younger than 1 wk (P = 0.95; n = 7;
Figs. 4B and 6). This confirmed that postsynaptic NMDA
receptors play a crucial role in this action of NT-3. Consistent with
the blockade of NT-3's action by NMDA receptor antagonists, NMDA
itself mimicked the action of NT-3 by enhancing fast DR-EPSPs (P = 0.02; n = 8; Fig. 6). Although
this effect was not significant on applying the strict Bonferroni
criterion, the potentiating effect of NMDA was observed in all eight
cells tested (mean increase = 36 ± 12%).
The potentiation of the monosynaptic EPSP induced by NT-3 persisted
after APV was added to the bath (Fig. 5C). A small reduction in the amplitude of the monosynaptic EPSP was detected in all five
cells tested (7.8 ± 1.9%; P = 0.02;
n = 5) (Fig. 5), but this decrease was much smaller
than the increase produced by NT-3 in the absence of APV. Thus, NMDA
receptors are required for initiation of the long-lasting NT-3 effect
on peak amplitude of fast DR-EPSPs, but not for its maintenance. In
all of these respects, the effect of NT-3 resembles long-term
potentiation (LTP) studied at other synapses (for review see
Malenka and Nicoll 1999
).
To examine whether NT-3 produces a direct action on motoneuron NMDA receptors, we studied the effect of NT-3 on NMDA-induced depolarization of the motoneuron in the presence of bath-applied tetrodotoxin (TTX) to block impulse activity in spinal neurons presynaptic to the motoneuron. Administration of 20 µM NMDA for 1 min produced a moderate, reproducible depolarization of 5-10 mV that was blocked by d-APV. NT-3 enhanced NMDA-induced depolarization in all three motoneurons tested by an average of 86 ± 17% (n = 3, P < 0.05; paired t-test, Fig. 7A). There was no sign of synaptic noise (Fig. 7A) that would have suggested increased presynaptic release of glutamate, as was observed in the absence of TTX (not illustrated). Also, application of NT-3 never depolarized the motoneuron, indicating that its action on the motoneuron is one of modulation rather than activation.
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DISCUSSION |
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We provide direct physiological evidence that brief administration
of NT-3 rapidly induces a synapse-selective and age-specific enhancement of fast synaptic transmission in the neonatal rat spinal
cord. The data support a mechanism whereby NT-3-induced synaptic
facilitation of the fast AMPA/kainate receptor-mediated DR-evoked
synaptic responses results from modulation of motoneuron NMDA receptors
by NT-3. The requirement for NMDA receptors, the persistence of the
increase in AMPA/kainate receptor-mediated EPSP amplitude despite
subsequent blockade of the NMDA receptor, and the long-lasting increase
induced by a brief pulse of NT-3 all point to a mechanism similar to
that responsible for LTP in area CA1 of the hippocampus (Malenka
1991).
NT-3 has also been found to elicit long-lasting changes in synaptic
transmission in the adult hippocampus that resemble LTP (Kang
and Schuman 1995), although the evidence there indicates that
the NT-3-evoked LTP is at least partially independent of the
stimulus-evoked LTP at CA1 synapses. First, unlike stimulus-evoked LTP,
NT-3 could produce LTP in the presence of APV, indicating an effect
independent of the NMDA receptor (Kang and Schuman
1995
). Second, antibodies to NT-3 did not have any effects on
the stimulus-evoked LTP (Chen et al. 1999
). Our present
findings indicate that NT-3-induced long-lasting enhancement of
synaptic transmission in the spinal motoneuron resembles
stimulus-evoked LTP at the Schaffer-collateral CA1 synapses in that
both processes require NMDA receptors.
LTP induced by high-frequency dorsal root stimulation has also been
reported in motoneurons of neonatal rats (Lozier and Kendig 1995). As in the hippocampus, the properties of LTP induced by stimulation and by NT-3 differ considerably. Stimulus-induced LTP in
motoneurons is confined to a very late component of the synaptic
response elicited by stimulation of C fibers. Unlike NT-3, repetitive
stimulation did not potentiate the short-latency, CNQX-sensitive
component of the EPSP. Furthermore, potentiation of the late response
by high-frequency stimulation occurred in the presence of APV, unlike
its complete blockade of NT-3-induced potentiation.
Neurotrophins have previously been suggested to affect central synapses
via NMDA receptors either indirectly by interaction at the level of
intracellular signaling cascades (Suen et al. 1997) or
directly at the glycine site of the NMDA receptor (Jarvis et al.
1997
) (Fig. 7B). Although we found that NT-3
enhances the initial AMPA/kainate response evoked by stimulation of the
dorsal root (Figs. 2 and 6), the requirement for NMDA receptors in
motoneurons to obtain this effect (Fig. 4) and the ability of NT-3 to
enhance the response of motoneuron NMDA receptors (Fig. 7A)
together indicate that the direct action of NT-3 in this system is also
on NMDA receptors. Also in agreement with the present scheme (Fig.
7B) are reports that activation of NMDA receptors can
increase the response of AMPA receptors (Benke et al.
1998
). Our results suggest that these two mechanisms can
operate in series, i.e., neurotrophins modulate NMDA receptors which in
turn increase the response of AMPA/kainate receptors to synaptically
released glutamate (Fig. 7B).
The finding that K-252a eliminated the response to NT-3 suggests that it was mediated by the high-affinity trkC receptor. A possible role for the p75 receptor was not considered directly but the finding that no other neurotrophin elicited this effect suggests that the p75 receptor is not a crucial component of the response since it is responsive to all neurotrophins.
Although details of the cellular mechanisms mediating these actions
remain obscure for the present, the NT-3 effects probably involve
signaling cascades related to intracellular calcium because chelating
Ca2+ in the motoneuron by BAPTA loaded into the
electrode prevented NT-3 potentiation of the monosynaptic fast EPSP
(Fig. 3B). Ca2+ entering via NMDA
receptors initiates the signaling cascade that results in enhanced
AMPA/kainate responses. For example, in the hippocampus,
Ca2+ influx through the NMDA-type ion channel can
activate CaM-kinase II (Strack and Colbran 1998), which
in turn can phosphorylate and regulate AMPA/kainate-type GluR ion
channels (McGlade-McCulloh et al. 1993
; Raymond
et al. 1993
; Stricker et al. 1999
). An alternate cellular mechanism for interaction of NMDA and AMPA receptors can
involve cytoplasmic C termini of AMPA-receptor subunits and the
glutamate receptor interacting protein (GRIP) (Li et al.
1999
). Postsynaptic NMDA receptors have recently been shown to
play a role in the accumulation of postsynaptic AMPA receptors, and the increase in the magnitude of the EPSP they evoke as a consequence of
LTP (Shi et al. 1999
). Despite the evidence for a
requirement for postsynaptic NMDA receptors in the changes reported
here, at the present time we cannot discard the possibility that
activating NMDA receptors in the postsynaptic cell retrogradely causes
the presynaptic terminal to increase release of transmitter
(Malgaroli et al. 1992
; Robert 1998
).
The effects of NT-3 were highly selective. NT-3 was unable to influence
the AMPA/kainate-mediated EPSPs produced by activation of the
descending fibers in the ventrolateral funiculus in the very same
motoneurons whose AMPA/kainate-mediated EPSPs from the dorsal root were
strongly facilitated (Fig. 2). Also, NT-3-facilitated DR-EPSPs only in
very young animals (<1 wk, Fig. 6). One possibility is that
trkC receptors are located in dorsal root afferents, but not
in the descending fibers, and these receptors in the dorsal roots
decrease in number during development and cannot mediate the effect of
NT-3 beyond the initial postnatal week. However, high expression levels
of trkC receptors have been found in lumbar dorsal roots in
3-mo-old rats (Bergman et al. 1999) and in the descending pathways as well (King et al. 1999
).
Moreover, in adult cats it is known that NT-3 applied directly to
axotomized afferent fibers can reverse the decline in conduction
velocity and EPSP amplitude associated with such damage (Mendell
et al. 1999
), indicating that trkC receptors
associated with spindle afferents remain functional, at least in adult
cats. This suggests that the changes are in NMDA receptors and there is
considerable evidence that these undergo substantial changes on their
subunit composition (Flint et al. 1997
; Monyer et
al. 1994
) and a decline in their sensitivity (Carmignoto and Vicini 1992
; Crair and Malenka 1995
;
Feldman and Knudsen 1998
; Hestrin 1992
;
Tsumoto et al. 1987
) in the first two postnatal weeks.
Thus, as things stand at present, it seems more likely that the
synapse-specific and age-specific effects noted here are due to
differences in NMDA receptor properties rather than trkC
receptor expression. We speculate that NMDA receptor properties must be
highly specialized according to the nature of the presynaptic input (DR
versus VLF in neonates).
To understand the role of NT-3 in normal function, it is important to
know where it is expressed. Its expression in adult muscle is well
established, particularly in association with spindles (Copray
and Brouwer 1997), which suggests that its role may be to
maintain the monosynaptic reflex pathway as well as other spindle projections. There is increasing evidence that NT-3 is also expressed in cells of the spinal cord, specifically in astrocytes of the white
matter and in motoneurons as well as smaller cells in the gray matter
(Scarisbrick et al. 1999
; Schober et al.
1999
). The persistence of the change induced by NT-3 during the
initial postnatal week raises the possibility that this mechanism
participates in the strengthening of DR connections to motoneurons
known to be occurring in neonatal rats at that time (Seebach and
Mendell 1996
). Together, these recent findings raise the
possibility that NT-3 is available in the vicinity of these synapses
and can exert actions on the monosynaptic reflex connection. However,
whether it is released in sufficient amounts and whether it exerts
physiological effects during development and/or in the adult is not yet known.
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ACKNOWLEDGMENTS |
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We thank Dr. Paul Adams for valuable comments on a draft of the manuscript and the Statistical Consulting Unit in the Department of Applied Mathematics and Statistics at the State University of New York at Stony Brook for help with the statistical procedures. Neurotrophins were received courtesy of Regeneron Pharmaceuticals Inc.
Support was provided by National Institute of Neurological Disorders and Stroke Grant NS-16696 to L. M. Mendell (Javits Neuroscience Award) and by the Christopher Reeve Paralysis Foundation. Additional support was provided by NINDS Grants RO1 NS-32264 and PO1 NS-14899 to L. M. Mendell.
Present address of B. S. Seebach: Dept. of Biology and Microbiology, University of Wisconsin at La Crosse, 1725 State St., La Crosse, WI 54601.
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FOOTNOTES |
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Address for reprint requests: L. M. Mendell, State University of New York at Stony Brook, Life Sciences Building, Room 550, Stony Brook, NY 11794-5230 (E-mail: lorne.mendell{at}sunysb.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 29 December 1999; accepted in final form 25 April 2000.
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REFERENCES |
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