Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2679_Библиотеки_им_академика_М_И_Перельмана
.pdf
This page intentionally left blankThis page intentionally left blankThis page intentionally left blankThis page intentionally left blank
https://t.me/medicina_free
News and Views
https://t.me/medicina_free
Chapter 4
Silent Synapse
Research from Washington University on phantom pain raises new questions about your high-school gym teacher’s proclamations that pain is “all
in your head.” The study found that chemical signals from the brain can
condition nerve synapses in the spinal cord so that pain persists even in
the absence of a stimulus. While investigators have known that the brain
effectively reduces pain by inactivating synapses, few have considered
the effect of the brain on enhancing signals of pain throughout the
87
88 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
nervoussystem. Dr. Min Zhuo and his team found that a region in the
brain of rats could activate neurons in the spinal cord, causing feelings of
pain without an apparent source [2]. In the study, Zhuo, along with
research assistantPing Li,showed that the rostroventral medulla region of
the brain sends a serotonin signal to the dorsal horn of the lumbar spinal
cord. Here, the signal reactivates the so-called “silent,” or inefficient, synapses at nerve junctions. This finding is significant because it provides
insight as to why some patients continue to experience pain even when the
stimulus is gone, Zhuo says. For example, cancer patients often have persisting pain even after tumors are removed. “Through the process we call
‘long-term potentiation,’ neurons in the spinal cord become efficient for
transmitting pain,” he says, “Once ‘silent’ synapses have been activated
during tissue or nerve injury, they tend to remain functionally active and
continue to send messages to the brain even when there is no stimulus to
speak of.” Zhuo says the research could have significant clinical implications because it suggests new targets and pathways for therapies aimed at
treating chronic pain.
Reported by: The Scientist (1998).
Summary
Neurons in the superficial dorsal horn of the spinal cord are important for
conveying sensory information from the periphery to the central nervous
system. It has been proposed that some synapses between primary afferent
fibers and spinal dorsal horn neurons are inefficient or silent. Ineffective
sensory transmission could result from a small postsynaptic current that
fails to depolarize the cell to the threshold for an action potential or a cell
with a normal postsynaptic current but an increased threshold for action
potentials. One possible mechanism for ineffective synapses may be due
to silent glutamatergic synapses. In silent synapses, postsynaptic dorsal
horn neurons lack functional AMPA/KA receptors, and no synaptic
responses are detected even when glutamate is released from presynaptic
sensory afferent fibers. Serotonin (5-HT), a major neurotransmitter of
theraphe-spinal projecting pathway, transforms silent glutamatergic synapses into functional ones by recruiting postsynaptic functional AMPA
receptors. AMPA receptor interaction with PDZ-containing proteins is
Silent Synapse 89
https://t.me/medicina_free
critical for 5-HT-induced recruitment. Silent synapses, as well as their
recruitment mechanisms, are developmentally regulated and can still be
found in adult synapses. However, they are “functional” and contribute to
some sensory transmission. The recruitment of AMPA receptors into pure
NMDA receptors containing sensory synapses requires the coactivation of
5-HT and postsynaptic ACs. The recruitment of silent glutamatergic synapses provides a synaptic mechanism for spinal sensitization in pathological pain, including possible phenotype switching of dorsal horn neurons.
These results suggest that the transformation of silent glutamatergic synapses may serve as a cellular mechanism for central plasticity in the spinal
cord.
Keywords: Silent synapse; AMPA receptor; Spinal cord; serotonin;
descending facilitation; cAMP; glutamate
Introduction
Primary afferent fibers form synapses with dorsal horn sensory neurons in
the spinal cord. Some of these dorsal horn neurons send ascending projecting fibers that synapse with neurons located at supraspinal sites, such
as the thalamic nuclei. These ascending pathways are important for conveying sensory information from the periphery to the brain (see Chapters
1–3). Dorsal horn sensory synapses receive descending modulation from
supraspinal structures. Most of these descending modulatory influences
relay at brainstem nuclei including the RVM (Chapter 1). Activation of
these modulatory systems could facilitate, or inhibit, spinal nociceptive
transmission and behavioral reflexive responses to noxious stimulation
depending on the stimulation parameters used. Thus, the fine regulation of
dorsal horn sensory synaptic transmission not only affects the amount of
information entering the brain but also influences the behavioral responses
to such stimuli.
Glutamate is a major neurotransmitter between primary afferent fibers
and dorsal horn neurons [1–3]. Postsynaptic sensory responses are mainly
mediated by glutamate AMPA/KA and NMDA receptors (see Chapter 3).
Glutamatergic synapses are heterogeneous in the spinal dorsal horn. At
least three different types of glutamatergic synapses are found: (1) Silent
synapses: in some synapses, only functional NMDA receptors are found.
90 Chronic Pain: New Molecular Insights into Pain and Treatment
https://t.me/medicina_free
Neither AMPA nor KA receptors are present, or functional, in these synapses. (2) AMPA receptor-containing synapses: at sensory synapses that
receive low-threshold inputs, only AMPA receptors are found and no
functional KA receptors exist. (3) KA/AMPA receptor mixed synapses: at
synapses receiving high-threshold inputs, both AMPA and KA receptors
are found. In both (2) and (3), NMDA receptors are always detected.
Besides being reliable and fast, glutamatergic synaptic transmission in
the spinal cord is dynamic and plastic. Recent progress in molecular and
cellular aspects of glutamate receptors shows that postsynaptic glutamate
receptors are put into the place through a family of proteins containing
PDZ domains. Furthermore, these postsynaptic protein–protein interactions are very dynamic and may be involved in the clustering, removal, or
insertion of postsynaptic receptors, providing a novel and efficient way to
regulate synaptic strength. This type of interaction could switch the phenotype of dorsal horn sensory synapses, i.e., changing silent synapses into
functional synapses. In this chapter, silent glutamatergic synapses in spinal dorsal horn neurons will be reviewed, and their possible physiological
functions will be discussed.
Spinal LTP
Studies of spinal LTP and its related synaptic mechanisms are limited by
the technical difficulty related to spinal cord slices and the complexity of
the local spinal neuronal network. Electrophysiological experiments using
intracellular, or whole-cell patch-clamp, recordings from the spinal dorsal
horn neurons generate some important findings related to spinal LTP [4–6]
(see Table 1). Strong tetanic stimulation (100 Hz, 1 sec for three times at
10-sec intervals) of the dorsal root induces long-lasting enhancement of
synaptic responses to presynaptic stimulation. The enhancement is relatively long-lasting (ranging from 25 min to 90 min) and input-specific.
Postsynaptic depolarization of dorsal horn neurons is critical for the induction of spinal LTP. Pairing postsynaptic depolarization with synaptic activity also induces long-lasting enhancement of synaptic responses (Figure 1).
Interestingly, the level of postsynaptic depolarization may be important in
Silent Synapse 91
https://t.me/medicina_free
Table 1. Experimental protocols for inducing LTP in the spinal cord.
Stimulation site Response Protocol Refs.
Dorsal root C response HFS (100 Hz for 1 second, three
times with 10-s interval)
Dorsal root C response LFS (2 Hz for 2 minutes) [27]
Entry zone Unidentified Pairing protocol (80 pulses at 2 Hz
with postsynaptic depolarization
at + 30 mV)
Entry zone
C and Aδ
responses
Spike timing (paired three
presynaptic stimuli (10 ms ahead)
with three postsynaptic APs at 30
Hz, paired 15 times every 5 s)
[26]
[4]
Unpublished
data
determining whether synaptic transmission will be potentiated or depressed.
In some experiments, synaptic depression can also be induced by pairing
synaptic activity with modest postsynaptic depolarization.
The induction of spinal LTP requires the activation of NMDA receptors and/or the SP (NK1) receptors. Activation of NMDA receptors in
spinal dorsal horn neurons leads to increases in intracellular Ca2+.
Pretreatment of spinal cord slices with NMDA receptor antagonist AP5
prevents the induction of LTP. Activation of postsynaptic calcium signaling pathways is important, and the inhibition of postsynaptic calcium
signaling pathways blocked the induction of LTP. The contribution of SP
to spinal LTP is likely through enhancing NMDA receptor-mediated currents in spinal dorsal projecting neurons. The intracellular signal pathways of spinal LTP have yet to be identified and characterized (see
Table 2). Evidence from other studies indirectly indicates that several
protein kinases may be important for spinal LTP, such as phospholipiddependent protein kinase (PKC). Phorbol ester induces long-lasting facilitation of evoked EPSP or EPSC amplitude to the stimulation of presynaptic
fibers. One key mechanism for PKC-dependent spinal LTP is through the
recruitment of postsynaptic silent synapses or the insertion of AMPA
receptors. Possible presynaptic mechanisms of spinal LTP have not been
investigated.
92 Chronic Pain: New Molecular Insights into Pain and Treatment
(a) (b)
(c)
(e)
https://t.me/medicina_free
(d)
Figure 1. LTP recorded by whole-cell patch in mice. Activation of Erk for the induction
of LTP in the superficial dorsal horn neurons. (A) Diagram of a slice showing the placement of a whole-cell patch-clamp recording and a stimulation electrode in the superficial
dorsal horn of the spinal cord. (B) Schematic illustrating the induction protocol consisting
of 80 pulses at 2 Hz while holding at +30 mV (paired training). (C) LTP was induced by
paired training in the superficial dorsal horn neurons. (D) Summary result of the LTP
experiments under control conditions (n = 9 neurons). EPSC responses were averaged over
5 min intervals. (E) The MEK inhibitor PD98059 (50 µM) in the intracellular solution
completely blocked LTP induction (n = 7 neurons). EPSC responses were averaged over 5
min intervals. (c–e) Traces show averages of six EPSCs 3 min before (a) and 25 min after
(b) the paired training (arrow). The dashed line indicates the mean basal synaptic
responses. Error bars indicate SEM. (adapted from Wei et al. [4]).
Silent Synapse 93
https://t.me/medicina_free
Table 2. Synaptic mechanisms for spinal LTP.
Stimulation site Protocol Postsynaptic component Refs.
Dorsal root HFS NK1 receptor, PLC, IP3 receptor,
NMDAR, T-type VGCC
Dorsal root LFS PLC, PKC, CAMKII, IP3 NO [27]
Entry zone Pairing protocol MEK [4]
[26]
Spinal sensitization and synaptic potentiation
Studies of LTP in spinal dorsal horn neurons have drawn much attention
because it is believed that the potentiation of sensory responses after
injury may explain chronic pain. It has been consistently demonstrated
that the spike responses of dorsal horn neurons to peripheral stimulation
are enhanced after the injury, however, whether the enhanced spike
responses are simply due to enhanced synaptic transmission between the
DRG cells and dorsal horn neurons remains to be investigated. Unlike
synapses in other areas, such as hippocampus, synaptic potentiation in the
spinal dorsal horn neurons is not induced by strong tetanic stimulation.
Recent studies further show that LTP only occurs in some of the spinal
projecting cells [11]. Spinal cord dorsal horn neurons that did not express
SP receptors did not undergo potentiation. Furthermore, activation of NK1
receptors or NMDA receptors is required for LTP. However, in other areas
of the brain such as hippocampus and cortex, there is no requirement for
SP or any similar neuropeptide for the induction of NMDA receptordependent LTP (see Chapter 5). It will be important to investigate why
LTP cannot be induced at other neurons that do not express SP
receptors.
Spinal LTP caused by peripheral injury
In vivo field recordings, or in vitro spinal cord slice recordings, found that
noxious stimuli, inflammation, and nerve injury all induced LTP at the
spinal dorsal horn synapses (Figure 2). The induction of such spinal
LTP is controlled by descending inhibitory systems from supraspinal
94 Chronic Pain: New Molecular Insights into Pain and Treatment
(a)
(b)
https://t.me/medicina_free
(c)
(e)
(d)
Figure 2. LTP can be induced by low-frequency afferent barrage evoked by inflammation of peripheral tissue. Mean time courses of C fiber-evoked field potentials recorded
extracellularly in superficial spinal dorsal horn in response to electrical stimulation of left
sciatic nerve of deeply anesthetized adult rats with spinal cords and afferent nerves intact.
Subcutaneous injections of transient receptor potential vanilloid 1 channel agonist capsaicin (1%, 100 µl, n = 5) (a) or formalin (5%, 100 µl, n = 6) (b) into the glabrous skin at the
ipsilateral hind paw, within the innervation territory of the sciatic nerve at time zero
(arrows), induced LTP (closed circles), whereas injections of the respective solvents (open
circles) had no effect (n = 3 in each group). Conditioning electrical LFS (2 Hz, 2 min at C
fiber intensity) of sciatic nerve at time zero (arrow) also induced LTP (n = 28) (C), which
was prevented by NMDAR antagonist MK-801 [3 mg kg–1, intravenous (iv) infusion over
30 min: horizontal bar, n = 5] (D). A second conditioning LFS 4 hours later (arrow) was
partially effective in inducing LTP. NOS inhibitor NG-monomethyl-L-arginine (L-NMMA)
(100 mg kg–1 hour–1, iv infusion: horizontal bar, n = 5) (E) also blocked LTP induction.
This block was fully reversible, as shown by a second LFS 3 hours later (arrow) (adapted
from Ikeda et al. [27]).
Silent Synapse 95
https://t.me/medicina_free
structures. The induction of spinal LTP requires the activation of glutamate NMDA receptors and NK1 receptors. Both receptors raise the postsynaptic calcium level and trigger intracellular calcium-related signaling
pathways.
Early studies of ineffective synapses in the spinal cord
The existence of ineffective, or silent, sensory synapses in the spinal cord
dorsal horn was first proposed by P.D. Wall in 1977. Due to the limits of
the recording method at that time, it was unclear whether ineffective sensory transmission was a result of the failure of a small postsynaptic current to depolarize a neuron to action potential threshold or because of an
increased threshold in a neuron with normal synaptic responses. Further
indirect evidence for silent synapses comes from intracellular recordings
of synaptic responses to stimulation of a single group of Ia afferents in cat
spinal motor neurons. To examine the size fluctuations of excitatory postsynaptic potentials (EPSPs), an application of 4-AP or tetanization of the
afferent led to the discovery that some previously ‘silent’ synapses
became active following stimulation. Despite the limitations of these
recording techniques, these studies provide strong evidence for the existence of silent synapses in the central nervous system. Considering the
high-level difficulty of spinal cord preparations, however, only a few studies have followed up on these initial findings.
Silent glutamatergic synapses in the spinal cord
dorsal horn
By using whole-cell patch-clamp recording techniques in brain slices,
silent glutamatergic synapses are reported in various regions of the CNS
including the hippocampus, neocortex, spinal cord dorsal horn, and ventral horn motor neurons [2,7–13]. In silent synapses, no effective AMPA/
KA receptors are available to detect the release of glutamate from presynaptic terminals. Consequently, these synapses do not conduct synaptic
transmission at the resting membrane potential. The existence of such
synapses between sensory fibers and dorsal horn neurons was shown in
the lumbar spinal cord [2]. Sensory neurons in the superficial dorsal horn
Соседние файлы в папке Библиотека им академика М.И. Перельмана