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Motor Neurobiology of the Spinal Cord
12
How Does Nerve Injury
Strengthen
Ia-Motoneuron
Synapses?
Timothy C. Cope, Kevin Seburn,
and Charles R. Buck
CONTENTS
12.4.2.1.1 Axotomy
12.4.2.1.2 TTX Treatment
12.4.2.1.3 Conclusion
12.4.2.2 Neurotrophins
Function in Adult Animals
of Neurotrophins in Relation to the
Ia-MN Synapse
Neurotrophins
12.4.2.2.4 Effects of Manipulating Neurotrophins
and Neurotrophins
© 2001 by CRC Press LLC
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12.1 INTRODUCTION
Synapses made in the spinal cord by neurons whose axons are severed several
centimeters distant in the periphery can express substantial changes within hours of
the injury. At the synapses made between group Ia muscle stretch afferents and alpha
motoneurons (Ia-MN synapses), the excitatory postsynaptic potentials (EPSPs) are
significantly enlarged soon after and for several days following nerve section in adult
rats. 1–3 This observation has captured our attention for a variety of reasons. First,
the direction of change may represent a unique form of synaptic plasticity, whereby
presynaptic inactivity enhances synaptic strength. Second, the speed of change
demonstrates that steady-state synaptic strength can be adjusted on a time scale of
hours, suggesting close and continuous regulation of mature central synapses. Third,
the potential role of neurotrophins in the regulating function of mature synapses
might be significantly advanced in light of recent findings on neurotrophin expression
by primary afferents, motoneurons, and muscle, and changes in this expression
following nerve section. Fourth, the environment of change is uniquely relevant to
whole-animal behavior because the changes are observed in vivo .
12.2 THE Ia-MN SYNAPSE: A PERSPECTIVE
ON CONTINUED STUDY
The first intracellular records of postsynaptic potentials in the mammalian central
nervous system were obtained at Ia-MN synapses in studies reported by Eccles and
colleagues in 1952. 4 The unique experimental accessibility to function at these
synapses motivated hundreds of subsequent studies and elevated the Ia-MN synapse
to the status of the prototype synapse in the mammalian central nervous system.
Over the past 50 years, the Ia-MN synapse has provided crucial and novel insights
into central synaptic function. The following topics were significantly advanced at
the Ia-MN synapse: electrotonic decay of synaptic current in passive dendrites;
nonlinear summation of synaptic currents; frequency dependent modulation of syn-
aptic potentials; quantal nature of transmitter release; specificity of synaptic con-
nections; and presynaptic inhibition. The reader can find discussion of these and
numerous other examples in References 5–12.
While these historical considerations establish the early value of information
about the Ia-MN synapse, for some readers they may also raise the question, “Does
further examination of the long-studied Ia-MN synapse have a place in a book
dedicated to frontiers in neuroscience?” The answer in our opinion is undeniably
© 2001 by CRC Press LLC
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“yes.” First, our understanding of the normal operation and regulation of function
at this synapse remains incomplete. In the course of discussion of selected candidate
factors that establish and adjust steady-state synaptic strength, this chapter identifies
important areas of uncertainty; for example, the fundamental relation between effi-
cacy and activity at Ia-MN synapses is not yet settled. Making this determination
is not only key to understanding the basic cellular mechanisms of synaptic function
at this and, perhaps, at other synapses, but also it has important implications for
abnormal motor behaviors such as hyperactive tendon-jerk reflexes that follow spinal
injury and stroke. A second reason for our positive answer is that study of Ia-MN
synapses continues to provide exciting new information. For example, a recent study
of developing Ia afferents and motoneurons shows that these neurons have a matched
expression of particular genes when they come to innervate the same muscle. 13 This
observation suggests a mechanism by which synaptic connections might be specified
between Ia afferents and motoneurons, and perhaps between other neuron types in
the CNS. A third rationale for continuing study of the Ia-MN synapse is that this
synapse is uniquely suited to examination in the intact central nervous system of
living mammals. The Ia-MN synapse can be exploited to test the physiological
relevance of findings made in more reduced preparations, e.g., spinal or brain slices.
12.3 Ia-MN SYNAPTIC FUNCTION
In this chapter we attempt to advance understanding of the function and regulation
of central synapses by examining the injury-induced enlargement of EPSPs at the
Ia-MN synapse. We begin in this section by defining the composite Ia EPSP and by
assessing its usefulness as a measure of Ia-MN synaptic function. This section is
necessarily brief and not intended to provide the thorough discussion of details that
can be found in several earlier reviews. 5–12
It is important to keep in mind that while the EPSP enlargement under consid-
eration here was observed in rat, some of the relevant observations used to evaluate
this enlargement were made in cat. Although there are no clear indications of species
differences in Ia-MN synaptic function, greater assurance will require more data.
Indeed, it is not known whether Ia EPSPs are actually enlarged in the cat 1 week
after muscle nerve section as they are in the rat.
12.3.1 S YNAPTIC P ATHWAYS I NFLUENCING THE Ia* EPSP
MNs. 14 Further detail about
spindle-afferent synapses with MNs derives from studies of anesthetized adult cats,
wherein EPSPs produced by individual afferents are measured in MNs using the
spike-triggered averaging (STA) technique. 15 Physiologically identified group Ia
afferents generate EPSPs with monosynaptic latency at synapses made with MNs
supplying the same muscle as the afferent (homonymous synapses) and with MNs
innervating synergist muscles (heteronymous synapses). For example, each one of
α
© 2001 by CRC Press LLC
Included among the large number of sensory afferents innervating a single skeletal
muscle are the afferents supplying muscle spindles. Each spindle-bearing muscle
sends multiple spindle afferents, groups Ia and II, into the spinal cord, where the
afferents synapse with a variety of neurons including
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FIGURE 12.1 The composite Ia* EPSP and its contributing afferent pathways. The voltage
trace to the right was recorded intracellularly from a medial gastrocnemius motoneuron
(conduction velocity 50 m/s) upon stimulation (0.5 hz) of the lateral gastrocnemius soleus
nerve in an anesthetized adult rat. The trace is an average of 10 sweeps. Neither pre- nor
postsynaptic neurons were axotomized. Arrows estimate central latency of action potentials
conducted in afferent pathways from the time of their arrival at the spinal cord (onset of each
arrow) to the initiation of postsynaptic potentials (to the tip of each arrow). Solid arrow
identifies central latency for the monosynaptic Ia afferent pathway; broken arrow shows central
latency for other pathways (involving group Ia, Ib, and II primary afferents) and indicates the
potential for these pathways to contribute to the EPSP before it reaches its peak amplitude.
All pathways are represented in the diagram to the left, where the solid and broken lines
depict, respectively, the pathways that yield the central latencies shown as solid and broken
arrows superimposed on the EPSP. The asterisk in Ia* EPSP designates the potential contri-
bution from sources other than the monosyanptic Ia pathway.
V. 17–20
Electrical stimulation of selected muscle nerves produces composite EPSPs at
short latency that range in peak amplitude from less than 1 to 12 mV in cat lum-
bosacral MNs 21,22 and from less than 1 to around 5 mV in rat. 2,3,23 The functional
anatomy described above for single Ia afferents leads to the supposition that this
short-latency EPSP is the composite synaptic event 24 produced by groups of Ia
afferents that are activated by electrical activation of the nerve. This composite EPSP
is the event shown to enlarge after muscle nerve section, and the extent to which it
represents Ia-MN synaptic function requires careful consideration.
The strength of electrical stimulation required to activate all Ia afferents in a
muscle nerve will also activate group Ib and some group II afferents. In the rat, there
is no obvious demarcation in the distribution in conduction velocity for afferent
groups Ia and II, 25 making it likely that there is considerable overlap in the electrical
thresholds of these afferents. It is important then to consider the contribution from
these other afferents to the putative composite Ia EPSP ( Fig. 12.1 ). We begin by
estimating that monosynaptic EPSPs produced by single Ia afferents reach their peak
amplitudes typically 1.5 msec after Ia action potentials arrive at the dorsum of the
spinal cord. This latency includes conduction time through the spinal cord up to
initiation of the EPSP in a MN, i.e., the central latency, which for single Ia afferents
is commonly 0.7 to 0.8 msec and ranges from 0.4 to 1.1 msec. 26,27 Added to this is
the rise time of the EPSP, which from 10 to 90% of the peak EPSP averages between
µ
© 2001 by CRC Press LLC
60 Ia afferents from the cat medial gastrocnemius (MG) muscle makes homonymous
synapses with virtually all 300 MG MNs and heteronymous synapses with about
2/3 of approximately 450 lateral gastrocnemius-soleus (LG-S) MNs. 16 Amplitudes
of EPSPs produced by single Ia afferents range from ca. 1 to 600
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0.6 and 0.9 msec and ranges between 0.2 and 3.0 msec. 15,18,20,26 In comparison, the
central latency for synaptic potentials produced either monosynaptically for some
group II afferents, 28,29 or disynaptically for other group II afferents and for group Ib
and Ia afferents, ranges between 1.2 and 2.8 msec. 26,29 This means that synaptic
potentials, both inhibitory and excitatory, evoked electrically through pathways other
than the monosynaptic group Ia pathway, can be initiated before the group Ia EPSP
reaches peak amplitude ( Fig. 12.1 ). 3 0–32 These considerations make it plain that
multiple afferent pathways have the capacity to contribute to the rising phase and
peak amplitude of short-latency EPSP.
In addition to the extrinsic synaptic influences that act postsynaptically to modify
the short-latency EPSP, other effects may be introduced presynaptically as a result
of afferents that synapse with Ia afferents and produce presynaptic inhibition. 10 The
influence of tonic presynaptic inhibition on short-latency EPSPs is suggested by the
large increase (up to 60%) that is observed in these potentials soon after treatment
with a GABA B antagonist. 23,33
As for the contribution of the Ia-MN synapse to the short-latency EPSP, the
following indirect evidence suggests an important if not predominant contribution.
First, the mean amplitude of the composite EPSP produced by electrical stimulation
approximates that calculated as the product of the number of activated Ia afferents
and the average EPSP produced by each. 17,18 Second, the amplitude of the steady-
state EPSP evoked by muscle vibration, a stimulus that selectively activates Ia
afferents in cats, covaries with the short-latency composite EPSP produced by
electrical stimulation of the nerve. 34 Third, the strength of reflex contractions initiated
by muscle stretch varies among triceps surae muscles in a pattern that matches the
pattern of short-latency EPSP amplitudes distributed in this system. 35
Considering all of the above, we arrive at the perspective that the short-latency
composite EPSP is generated predominantly at Ia-MN synapses but modified by
transmission through other afferent pathways. In order to acknowledge potential con-
tributions from these other pathways we use an asterisk when referring to the composite
Ia* EPSP. Strong support for the assertion that the Ia-MN synapse itself contributes
to the axotomy-induced enlargement of the Ia* EPSP is given below (12.4.1).
12.3.2 O THER I NFLUENCES ON Ia* EPSP A MPLITUDE
Theoretical considerations identify several anatomical and biophysical properties of
both pre- and postsynaptic elements of the Ia-MN synapse that are expected to
influence Ia* EPSP size. These properties, e.g., MN cable properties and synaptic
density of Ia afferent terminations on MNs, have been the subject of extensive
discussion and study. 5,6,8,11,24 We expect that the explanation for Ia* EPSP enlarge-
ment resides in the changes induced by axotomy in one or several of these cellular
properties of the Ia-MN synapse, and some possibilities are discussed below (12.4.3).
Limited space precludes further discussion. Before continuing, however, we point
out that because of its dependence on multiple features of the Ia-MN synapse, the
amplitude of the Ia* EPSP is sensitive to a broad range of changes at the synapse.
This sensitivity has great value in enabling detection of synaptic plasticity. Knowl-
edge of the pre- and postsynaptic factors that covary with Ia* EPSP amplitude also
© 2001 by CRC Press LLC
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