04. ARTIGO I data 27 03 2018 sinapse axo mielínica

Prévia do material em texto

Once thought to be a mostly inert layer of 
insulation around axons, myelin is now 
considered to play an active and dynamic 
role in the preservation and maintenance 
of axonal structure and function1,2. We had 
previously reported the presence of NMDA 
receptors (NMDARs) in CNS myelin that 
were activated by reverse Na+-dependent 
glutamate and glycine transport during 
chemically induced ischaemia in 
white matter3,4. These results suggested 
that NMDARs expressed on myelin have a 
physiological purpose and could represent 
the receiving end of a potential, synapse-like, 
chemically dependent signalling interaction 
between the axon and its myelin sheath5. The 
mechanisms underlying the communication 
between axon and adjacent myelin 
membranes were unknown, but recently, 
studies have emerged that begin to shed 
light on the molecular architecture of this 
putative ‘axo-myelinic synapse’ (AMS), 
how it responds under normal (rather 
than pathological) conditions6 and its 
potential physiological roles1,6. Technical 
advances, particularly in high-resolution 
fluorescence imaging, have greatly increased 
axon1,6. Moreover, we postulate that this 
newly identified form of communication is 
vital to both myelin and axonal function and 
builds on an old evolutionary relationship 
between long neuronal processes and their 
associated glia9.
In higher vertebrates, the communication 
between axons and oligodendrocyte progenitor 
cells (OPCs) begins early in development. 
Here, synapse-like structures form between 
unmyelinated axons and OPCs10,11. Most of 
these synapses are transient, but some persist 
and, we propose, could transition to an AMS. 
Currently, we understand the AMS only in 
the context of glutamatergic signalling, and 
we hypothesize that this synapse serves a role 
in fine-tuning axonal conduction, possibly 
affecting aspects of learning and memory; 
this in turn could affect various neurological 
and psychiatric disorders. We discuss the 
development and physiology of the AMS, and 
we also speculate about how the AMS may 
play an important pathophysio logical role 
in diseases as diverse as multiple sclerosis, 
schizophrenia and Alzheimer disease (AD), 
where excess myelinic Ca2+ can cause subtle 
— or gross — alterations of the sheath3,12, 
potentially leading to abnormal function of 
the neuronal circuitry and ultimately 
neuro psychiatric disability.
Development of axo-myelinic coupling
Communication between cells via 
signalling molecules is a fundamental 
aspect of nervous system development. 
Although most commonly associated 
with communication between neurons, 
chemical neuro transmission has recently 
been shown to be more general, involving 
perisynaptic astrocytes as well as signalling 
between neurons and OPCs (FIG. 2). During 
development, both GABAergic13,14 and 
glutamatergic axons form synapse-like 
structures with OPCs (‘OPC synapses’)10,13,15. 
Similar to neuronal synapses, presynaptic 
activity, in this case axonal action potentials, 
stimulates axonal vesicular release of neuro-
transmitters, either GABA or glutamate, 
which bind to the postsynaptic receptors 
expressed on the surface of the OPC. 
At glutamatergic neuron–OPC synapses, 
glutamate activates AMPA receptors 
(AMPARs), resulting in current flow 
into OPCs10,15,16. Functionally, OPC synapses 
our understanding of this potentially vital 
interaction. Similar to classical synapses 
between presynaptic and postsynaptic 
neuronal structures, preliminary evidence 
suggests that certain myelinated axons secrete 
neurotransmitters in an activity-dependent 
manner, thereby activating corresponding 
receptors on the inner myelin surface and 
thus forming a potential AMS (FIG. 1); these 
structures likely occur along the length of 
the internodal axon. As an action potential 
travels along a fibre, it triggers a low-level 
glutamate release from the axon itself that 
activates glutamate receptors expressed on 
the myelin sheath6–8 and allows Ca2+ entry 
into the cytosolic compartment of myelin. 
In this way, mature oligodendrocytes and 
their myelin sheaths are potentially able to 
detect and respond to axonal spiking activity. 
One likely function of the AMS is to couple 
electrical activity to the metabolic output 
from the oligodendrocyte: as action potential 
traffic increases, more glutamate is released, 
which increases myelinic Ca2+ and triggers 
lactate release from the oligodendrocyte. 
Lactate is a metabolic fuel, and this process 
thus increases energy availability for the 
O P I N I O N
Axo-myelinic neurotransmission: 
a novel mode of cell signalling in 
the central nervous system
Ileana Micu, Jason R. Plemel, Andrew V. Caprariello, Klaus-Armin Nave and 
Peter K. Stys
Abstract | It is widely recognized that myelination of axons greatly enhances the 
speed of signal transmission. An exciting new finding is the dynamic communication 
between axons and their myelin-forming oligodendrocytes, including 
activity-dependent signalling from axon to myelin. The oligodendrocyte–myelin 
complex may in turn respond by providing metabolic support or alter subtle myelin 
properties to modulate action potential propagation. In this Opinion, we discuss 
what is known regarding the molecular physiology of this novel, synapse-like 
communication and speculate on potential roles in disease states including 
multiple sclerosis, schizophrenia and Alzheimer disease. An emerging appreciation 
of the contribution of white-matter perturbations to neurological dysfunction 
identifies the axo-myelinic synapse as a potential novel therapeutic target.
NATURE REVIEWS | NEUROSCIENCE VOLUME 19 | JANUARY 2018 | 49
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can also undergo a form of potentiation 
called glial long-term potentiation (LTP)17, 
which is analogous to LTP found at certain 
neuronal synapses.
Despite the early characterization of OPC 
synapses10, their physiological importance 
is still being studied. OPCs are the source 
of myelinating oligodendrocytes18,19, and 
therefore, OPC synapses were first thought 
to promote the differentiation of OPCs into 
oligodendrocytes or to increase myelination. 
OPC synapses are maintained during OPC 
migration and proliferation, and during the 
latter process, OPC synapses are inherited 
by the daughter cells from their parent, 
suggesting that OPCs are continuously 
monitoring axonal activity20,21. In vitro studies 
impaired; increased proliferation is linked 
to impaired myelination, suggesting 
that GABA stimulates oligodendrocyte 
differentiation by impairing proliferation24. 
Therefore, regulating OPC distribution 
during CNS development may be one 
important physiological function of 
axon–OPC synapses.
A long-suspected purpose of OPC–
axonal communication is to mediate 
activity- dependent myelination. 
Neuronal activity — experimentally 
enhanced using optogenetic strategies 
— drives OPC proliferation, oligodendro-
genesis and myelination of axons27. As OPCs 
are able to sense this activity via activi-
ty-dependent release of neurotransmitters, 
suggest that glutamate and GABA inhibit 
OPC proliferation22–24 and stimulate integrin- 
mediated migration25, which is perhaps a 
mechanism by which OPCs can be ‘captured’ 
by or excluded from axons with heightened 
spiking activity. An example of the latter 
is found in the development of the barrel 
cortex, the highly ordered representation of 
facial whiskers. Here, OPCs are excluded 
in an activity-dependent manner from 
regions enriched in neurons and synapses. 
Only after the loss of sensory input from 
whiskers are OPCs able to penetrate into 
these neuronal regions26. By contrast, 
OPC synapsesonto GABAergic cerebellar 
interneurons increase their proliferative 
capacity when GABA signalling is 
Figure 1 | Molecular architecture of the proposed axo-myelinic synapse. 
Depolarization of the internodal axolemma by traversing action potentials 
(step 1) is detected by voltage-gated Ca2+ channels (Cav) (step 2). Because 
of the insulating properties of the myelin wrapped around the axon, a rela-
tively low-resistance pathway must be present through the myelin sheath 
in order for the electric field change to be sensed by Cav (step 3). There is 
evidence to suggest that Cav exist in a physical association with ryanodine 
receptors (RyRs), and the main consequence of internodal Cav activation 
is to activate RyRs on the axoplasmic reticulum located near the inner sur-
face of the axolemma, resulting in intra-axonal Ca2+ release41 (step 4). This 
in turn promotes fusion of glutamatergic vesicles and release of glutamate 
into the periaxonal space, which then activates myelinic AMPA and NMDA 
receptors (AMPARs and NMDARs, respectively) mainly expressed on the 
innermost myelin leaflets (step 5), promoting Ca2+ influx into the myelin 
cytoplasm. Glutamate in the periaxonal space is then likely taken up by 
glutamate transporters (GluTs) for reloading into vesicles, and periaxonal 
levels of glycine (a co-agonist at the NMDAR) are set by glycine transport-
ers (GlyTs), thus modulating the activity of the NMDARs. Likely conse-
quences of myelinic receptor activation include recruitment of glucose 
transporter type 1 (GLUT1), increased glucose uptake and stimulation 
of glycolysis by the oligodendrocyte, resulting in increased production of 
pyruvate and lactate (step 6). The former could constitute an energy supply 
for myelinic mitochondria, while the latter is transported across the peri-
axonal space to the axon (step 7) to fuel aerobic metabolism by axonal 
mitochondria for the efficient production of ATP at internodes (step 8), 
where many essential ATP-requiring molecules such as the Na+/K+-ATPase 
are located. MCT, monocarboxylate transporter. Adapted with permission 
from REF. 6, Elsevier.
Oligodendrocyte
Nature Reviews | Neuroscience
1
3
2
8
7
4
5
6
Axoplasmic reticulum
AMPAR NMDAR
Cav
RyR
GluT
?
Axon
Periaxonal space
Myelin
GlyT MCT2
MCT1
GLUT1
Glycolysis
ATP
Glucose
Pyruvate
Glutamate
Glycine
Cl–
Na+
K+
Lactate
H+
Ca2+
Action potential 
Low-resistance 
pathway
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it was suspected that these synapses might 
dynamically regulate myelination. Somewhat 
surprisingly, there is only sparse evidence 
for such an assumption. Glutamatergic 
stimulation has been associated with 
enhanced translation of myelin basic protein 
(MBP) mRNA in newly differentiated 
oligodendrocytes and with the onset of 
myelination11. In addition, preventing 
axonal vesicular release during zebrafish 
development can decrease the number 
of sheaths produced by an individual 
oligodendrocyte and attenuate myelination28. 
However, other neuronal subtypes regulate 
myelination by different mechanisms, as 
preventing vesicular release does not alter 
myelination in all neuronal populations29. 
Moreover, in mice, conditional removal 
of NMDARs from OPCs did not alter 
myelination in the brain, although a 
caveat of this study is that OPC synapses 
still formed, with only minor changes in 
their excitability in the absence of functional 
OPC NMDARs30. Prior stimulation by 
neuregulin 1 appears to determine whether 
or not NMDAR-driven, activity-dependent 
myelination occurs, at least in vitro, further 
adding to the complexity31.
As glutamatergic OPC synapses are 
AMPA-dependent10,16, blockade of either 
spiking activity or AMPARs decreases 
myelination in culture22. Recently, it was 
shown that the conditional removal of 
AMPAR subunits from oligodendrocyte 
oligo dendroglial process and that this later 
turns into a ‘myelinic synapse’ for continued 
axon–myelin communication in the 
mature nervous system. This arrangement 
permits axonal action potentials to induce 
vesicular release of glutamate from the 
internodal axon into the periaxonal space 
under the myelin, which can then activate 
myelinic glutamate receptors6. This novel 
arrangement thus supports the transduction 
of an electrical signal within a neuronal 
element into a chemical signal, which in 
turn induces a Ca2+ fluctuation in a target 
cell (the myelin compartment). As such, 
this framework bears resemblance to 
conventional synapses between neurons 
despite apparently not containing all the 
sophisticated molecular machinery of 
the latter. Although ultrastructural data 
indicate infrequent internodal vesicles, 
calculations suggest that the contents of only 
a single glutamatergic vesicle, discharged 
and evenly distributed along the periaxonal 
space, would be sufficient to begin activating 
myelinic NMDARs6. Another interesting 
difference between the proposed AMS and 
conventional synapses, forced upon the 
axon by virtue of its tight myelin wrapping, 
concerns the availability of Ca2+ required 
for neurotransmission. The molecular 
machinery responsible for vesicular fusion 
and transmitter release requires Ca2+ ions, but 
in contrast to readily available extracellular 
Ca2+ at neuronal synapses35, rapid access 
lineage cells did not alter OPC proliferation 
or density but instead compromised 
oligodendrocyte survival, suggesting 
that glutamate promotes the survival of 
newly differentiated oligodendrocytes32. 
Interestingly, as OPCs differentiate into 
pre-myelinating oligodendrocytes and 
subsequently into mature oligodendro-
cytes, synchronous synaptic currents 
detected at their somata largely vanish33, 
yet activity-dependent vesicular release 
can strengthen and maintain myelination 
at local ensheathment sites34. Together, 
these observations suggest a ‘centrifugal’ 
migration of glutamate receptor signalling 
from the soma to more distal regions of 
the oligodendrocytic processes and myelin 
as these cells mature and myelination 
progresses (FIG. 2). This would be a logical 
redistribution of receptors because after 
myelination is complete, unlike OPCs, mature 
oligodendrocyte cell bodies would have little 
opportunity to sense the glutamate released 
from electrically conducting axons that would 
then be almost completely covered by myelin. 
Consistent with this notion, axonal glutamate 
release regulates local MBP translation 
distally within the oligodendrocyte processes 
at ensheathment sites11.
Molecular physiology
We propose that this neuron–OPC synapse 
occurs when the ‘postsynaptic’ OPC 
compartment transforms into a growing 
Figure 2 | Hypothetical transition from OPC synapse to axo-myelinic 
synapse. Left: In oligodendrocyte progenitor cells (OPCs), axonal activity 
can be monitored via synaptic communication. In pre-myelinated axons, 
the arrival of an action potential results in axonal glutamate release, 
dependent on Ca2+ entry through voltage-gated Ca2+ channels16. Once 
released, glutamate diffuses across the synaptic junction to activate AMPA 
receptors (AMPARs) expressed on OPC processes and elicits inward ionic 
current that can be detected in the soma. Middle and right: As OPCs dif-
ferentiate and mature, inward currents are no longer detected using whole-
cell recordings from the soma. Still, during early myelin development, there 
are synaptic puncta that are located underneath ensheathmentsites34. 
These myelin ensheathments overlying synaptic puncta might contain 
AMPARs and NMDA receptors (NMDARs; the hypothetical presence of 
these receptors is indicated by question marks on the figure), which would 
provide a conduit for ions — including Ca2+ — to enter into immature mye-
lin. The release of glutamate into the periaxonal space between the axon 
and immature myelin is likely, given the presence of voltage-gated Ca2+ 
channels along the axolemma adjacent to vesicles40. Such structures would 
provide for a precursor to what ultimately could become an axo-myelinic 
synapse.
NMDAR
AMPAR
Oligodendrocyte
progenitor cell
Ensheathing
oligodendrocyte 
Ionic
current
Ionic
current Ionic
current
Myelinating
oligodendrocyte 
Nature Reviews | Neuroscience
? ?
Myelin development and maturation
NucleusSoma
OPC
process
Exocytosing
vesicle
Axon
Cav
GlutamateAction potential 
Ca2+
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of the internodal axon to extracellular 
ions is severely restricted because of the 
overlying myelin. However, myelinated 
axons contain an extensive internal network 
of Ca2+-containing cisternae, termed 
the axoplasmic reticulum, which is the 
equivalent of the endoplasmic reticulum in 
other cells36. The purpose of the axoplasmic 
reticulum is not clear, but one plausible role 
may be as a source of intracellular Ca2+ for 
vesicular release of transmitters from the 
internodal axon. Indeed, voltage-gated Ca2+ 
channels and AMPARs are expressed on the 
internodal axolemma37–40 and are able to sense 
depolarization and permeate small amounts 
of Ca2+ ions. These ions function to release 
additional Ca2+ via ryanodine receptors on the 
axoplasmic reticulum via a depolarization- 
induced41 and a Ca2+-induced42 Ca2+ release 
mechanism. In this way, the axon would 
elegantly work around its restricted access to 
extracellular Ca2+.
On the ‘postsynaptic’ side, the inner 
tongue of the myelin sheath contains 
receptors of the AMPA and NMDA 
classes that can respond to glutamate (and 
glycine) fluctuations in the periaxonal 
space. Activation of these receptors on the 
adaxonal myelin, that is, the wrap of myelin 
closest to the axon, results in a Ca2+ increase 
within the thin cytosolic space of the myelin 
spiral. This occurs in the intact optic nerve 
under physiological conditions of action 
potential traffic along the parent axon6 and 
to an even greater extent during pathological 
conditions such as chemical ischaemia3; 
notably, NMDAR activation does not 
elevate Ca2+ in the oligodendrocyte 
soma43, further supporting the notion of a 
centrifugal, myelinic distribution of 
these receptors as these cells mature. 
This finding has potentially important 
implications for white-matter physiology 
and pathophysiology (see later sections). 
A coincidence detection model akin to that 
originally described in neurons, in which 
AMPAR-mediated depolarization relieves the 
Mg2+ ion block from NMDARs — as weak as 
it might be for myelinic NMDAR subtypes, 
as the GluN3A subunit plays a prominent 
role in myelinic Ca2+ signalling44, and such 
receptors exhibit a weaker Mg2+ block8. 
Given that AMPAR-mediated depolarization 
may not be as robust in myelin as in neuronal 
synapses, expression of NMDARs with 
weaker Mg2+ sensitivity may be needed 
to limit voltage-dependent blockade and 
allow sufficient activation, allowing Ca2+ 
entry through the latter. This appears to 
also be the case in myelin; stimulation of 
either AMPARs of NMDARs is sufficient 
— required to establish transmembrane 
potentials and essential components of 
electrochemical signalling — further bolsters 
the notion that myelin is an electro chemically 
active postsynaptic partner in the AMS. 
Taken together, the unusual architecture 
of myelin, with both compacted and 
nanometre-wide cytosolic compartments, 
suggests that most relevant electrochemical 
and biochemical signalling occurs at the inner 
myelin tongue, where the cytosolic space is 
more substantial and where many receptor 
proteins, transporters and cargo-transporting 
microtubules are located.
Functions of the axo-myelinic synapse
Because conducting axons release trace 
amounts of neurotransmitter underneath the 
myelin as a function of spike frequency6, 
the AMS has the potential to communicate the 
average activity rate to the enveloping myelin 
sheath and perhaps, via its nanochannels, 
to the soma of the parent oligodendrocyte. 
This could elegantly regulate two putative 
functions of oligodendrocytes in myelination 
and axonal metabolic support.
Activity-dependent metabolic coupling. 
As discussed for Ca2+ ions above, the physical 
barrier of myelin would also pose major 
challenges to the timely supply of substrates 
to meet the substantial metabolic needs 
of active axons, especially at high firing 
rates. Given that the length of axons can 
extend to many centimetres, the delivery 
of substrates by passive diffusion from 
the neuronal somata would not be viable. 
Alternatively, considering the optic nerve, 
calculations suggest that here, axons can take 
up glucose at nodes of Ranvier (where the 
fibre is not enveloped by myelin) at rates that 
are sufficiently high that additional oligo-
dendroglial support may not be necessary53. 
These estimates build on numerous 
assumptions, including the average axon 
calibre and lengths of internodes and nodal 
regions in the optic nerve, the unknown 
density of glucose transporters in the axonal 
membrane and mean firing rates of retinal 
ganglion cells in the 3–4 Hz range. However, 
other neurons have axons that differ in 
calibre and fire at much higher frequencies 
(100 Hz and beyond)54. Moreover, mean 
firing rates do not reflect the necessity for 
some axons to transiently increase their 
action potential frequencies to even higher 
rates (>300 Hz)55, though frequencies in 
the tens of hertz are probably more typical. 
Although the nodal presence of glucose 
and monocarboxylate transporters is not 
well established, assuming nonetheless that 
to promote myelinic Ca2+ accumulation. 
Conversely, NMDAR blockade alone, or 
genetic deletion of the GluN2D and/or 
GluN3A subunits, is sufficient to prevent 
most of the rise in myelinic Ca2+ (even in 
response to AMPAR activation alone), 
indicating that NMDARs are the dominant 
and final Ca2+ influx pathway6,44. However, 
these experiments did not involve deletion 
of the genes encoding GluN subunits 
specifically in oligodendrocytes, raising the 
possibility that myelin Ca2+ increases could 
have occurred indirectly via axonal NMDAR 
signalling. However, given the unequivocal 
presence of both AMPARs and NMDARs on 
myelin3,6,7, these data strongly suggest that 
direct activation of these receptors was mainly 
responsible for the observed Ca2+ signals in 
the sheath. It should also be mentioned that 
a recent report by Hamilton and colleagues43 
questioned whether NMDAR activation 
produces a Ca2+ rise in the processes of 
oligodendrocytes. Key differences in 
experimental technique likely underlie 
the discrepancy: Hamilton et al. recorded 
from oligodendrocyte processes, applied 
100 μM NMDA without glycine and used 
1-photon excitation for their fluorescence 
measurements. By contrast, Micu et al. 
confirmed that optical recordings were from 
myelin per se using polarization 2-photon 
microscopy45, and they routinely applied 
lower concentrations of NMDA (20 μM) 
together withthe obligatory co-agonist 
glycine6, having also observed that higher 
NMDA (≥100 μM) failed to induce a 
myelin Ca2+ increase, likely due to receptor 
desensitization. The optical recording 
method itself exerts a profound effect on 
fluorescence from the myelin compartment, 
which requires polarization-controlled 
2-photon excitation; 1-photon excitation 
consistently failed to induce a measurable 
myelinic Ca2+ response45. Finally, regional 
differences (cerebellum43 versus optic 
nerve and/or dorsal column4,6) could also 
contribute to the conflicting observations.
Which Ca2+-dependent signalling 
pathways are subsequently activated within 
the myelin sheath, and what their effects are, 
is currently unknown. However, myelin does 
contain a variety of Ca2+-sensitive targets, 
such as Ca2+-sensing proteins (for example, 
calmodulin46), phospholipases, proteases 
(for example, calpains47) and protein arginine 
deiminases48, that are plausible targets 
of NMDAR-mediated Ca2+ fluctuations. 
Although receptor-mediated ion fluxes 
across myelin membranes may seem 
counter- intuitive, mounting evidence for 
ion-pumping activity49–51 and K+ channels52 
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energy-rich substrates enter into the axon 
exclusively at the nodes of Ranvier, diffusion 
times from the node to the internode could 
take many minutes for larger-calibre axons 
with long internodes. These distances are 
critical because the ATP-consuming Na+/K+ 
pumps and axonal mitochondria are largely 
localized in internodal regions. Thus, nodally 
sourced energy may be adequate for basal 
activity or for small-diameter myelinated 
axons with short internodes that normally 
fire at low frequencies. On the other hand, 
additional energy supplies that can deliver 
substrates rapidly from glial elements directly 
to the internode in response to transient 
increases in demand are likely vital to support 
the large dynamic range of firing frequencies 
of myelinated fibre tracts56. Observations 
on optic nerves whose oligodendrocytes 
were genetically depleted of NMDARs are 
consistent with this model (see below).
The axon degeneration phenotype 
of mice with myelin deficient in myelin 
proteolipid protein (PLP1) or 2ʹ,3ʹ-cyclic- 
nucleotide 3ʹ-phosphodiesterase (CNP1), 
but not MBP, led to the discovery that oligo-
dendro cytes support axonal integrity and 
survival independent of the physiological 
function of myelin57,58. The molecular 
mechanisms of this support have only 
recently begun to be understood. One 
metabolic substrate generated within oligo-
dendrocytes and their cytoplasmic extensions 
is pyruvate/lactate, which is supplied to 
the axonal compartment via myelinic 
nanochannels and monocarboxylate 
transporters, localized in adaxonal myelin 
(MCT1) and on the axolemma (MCT2)2,59. 
Lactate produced by glycolysis in oligo-
dendrocytes is thus reconverted in the 
axon to pyruvate and used to produce 
ATP via aerobic respiration in axonal 
mitochondria. In support of this process, 
the oligodendrocyte- specific removal of 
MCT1 results in axonal injury but not 
oligodendrocyte death, suggesting that 
lactate is exported from the oligodendrocyte 
into the axon and that this transport can be 
vital for axon survival60.
The above observations suggest 
that oligodendrocyte-sourced axonal 
energy production occurs in response 
to electrical activity itself. How can such 
activity- dependent metabolic coupling 
be quantitatively regulated? As described 
in the previous section, axonal action 
potentials activate myelinic NMDARs6. 
Interestingly, activation of NMDARs on 
the oligodendrocyte increases surface 
expression of glucose transporter type 1 
(GLUT1; also known as SLC2A1), the main 
Taken together, OPC differentiation 
and myelination are dynamically regulated 
by neuronal activity, but many of the 
underlying mechanisms remain to be 
defined. Recently, it was suggested that 
neuregulin 1 stimulates oligodendrocytes 
expressing epidermal growth factor receptor 
(EGFR; also known as ERBB) to switch into 
an activity-dependent mode of myelination 
by increasing the expression of oligo dendro-
glial NMDARs31. One could speculate that 
this latter effect could promote glucose 
import and thus metabolically facilitate 
membrane growth. Similarly, observations 
in living zebrafish suggest that activity- 
dependent axonal vesicular release increases 
the number and stability of myelin sheaths 
produced by each oligodendrocyte28,34.
The effect of neuronal activity on 
de novo myelination of axons by newly 
generated oligodendrocytes could, in 
turn, result in a subtle tuning of axonal 
conduction velocity resulting from minor 
alterations of the myelin and/or nodal 
architecture. This could be a mechanism 
by which the millisecond precision of 
long-range axonal projections is adjusted, 
as is required for spike- timing-dependent 
plasticity. However, this is currently a 
completely theoretical construct. Alterations 
in paranodal myelin that change node 
size75 could adjust conduction velocity 
without requiring the metabolic expense 
of producing additional myelin. The AMS 
may play a role in the structural plasticity of 
myelin by being in a position to detect action 
potential traffic, admitting Ca2+ into the 
myelin cytosol and stimulating a variety of 
Ca2+-dependent enzymes that could rapidly 
modulate the biochemical makeup of the 
sheath and therefore its nanoarchitecture.
Adult-born oligodendrocytes that 
generate new myelin sheaths in the brain, 
spinal cord and optic nerve have been 
detected in all vertebrates61,76 and may 
be necessary for myelin maintenance, 
remodelling and repair. The number of 
myelin sheaths that one oligodendrocyte 
can generate is controlled by several factors, 
including signalling by the tyrosine- protein 
kinase FYN and neuronal activity but also 
by vesicular release. Other intracellular 
signalling mechanisms implicated in 
myelin plasticity include phosphoinositide 
3-kinase, extracellular- signal- regulated 
kinase 1 (ERK1) and/or ERK2 (REFS 77,78) 
and Calcium/calmodulin- dependent 
protein kinase type II subunit β (CAMKIIβ). 
Interestingly, phosphoinositide 3-kinase, 
ERK1 and/or ERK2 and CAMKIIβ are all 
regulated by Ca2+, which could be controlled 
membrane glucose transporter in these cells1. 
This upregulation of GLUT1 occurs within 
minutes and augments glucose import, 
stimulating lactate release. The functional 
consequence of this mechanism is that in the 
absence of oligodendrocyte NMDARs — that 
is, without a fully functioning AMS — optic 
nerve axons fatigue more rapidly but only at 
higher stimulation rates. Neurons in other 
CNS areas even show spontaneous neuro-
degeneration in aged mice, suggesting that 
impaired metabolic coupling between the 
axon and oligodendrocyte is deleterious 
over a long period of time even under 
in vivo physiological conditions1. This points 
to a potentially crucial role for the AMS 
as a means of coupling the rate of action 
potential traffic to the oligo dendroglial 
generation and transfer of energy-rich 
substrates to the axon, particularly during 
periods of heightened electrical activity. 
Disruption of this mechanism, acutely or 
chronically, may have serious consequences 
for long-term axonal health. This could 
readily explain why genetic or acquired 
defects of myelin result in conduction 
abnormalities and axonal degeneration at 
times long before overt demyelination.
Myelin structuraldynamics. Myelination 
proceeds in a defined chronological and 
topographic sequence61,62, and it has been 
suggested that ‘basal’ myelination (driven by 
oligodendrocyte-intrinsic and environmental 
cues) is followed by a neuronal-activity-de-
pendent mode of ‘targeted’ myelination 
that fine-tunes axon ensheathment during 
learning and memory consolidation11 
(reviewed in REF. 63). At a functional and 
macroscopic level, piano playing, juggling, 
visuomotor training64,65 and learning 
language and mathematics66,67 have all been 
associated with increased white-matter 
volume in specific regions of the brain 
as measured by MRI in healthy adults. 
Conversely, decreased sensory input as in 
adults who are deaf or blind results in lower 
white-matter volume in relevant areas68,69 
and is reflected by hypomyelination in 
socially deprived mice70,71. Indeed, learning 
new motor skills or spatial navigation 
tasks is sufficient to increase myelination 
in specific regions72. In mice, it has been 
genetically demonstrated that new motor 
learning requires OPC differentiation and 
myelination73. Corresponding to these 
functional experiments, it was shown at 
the cellular level that electrical activity of 
neurons promotes the proliferation of OPCs 
and myelination of axons both in vitro74 and 
following optogenetic stimulation in vivo27.
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by Ca2+-permeable myelinic NMDARs. 
This establishes a potential biochemical 
framework for the transduction of axonal 
activity into structural modulation of the 
overlying sheath that could tune conduction 
velocities, for example, for network 
synchronization or synaptic strengthening. 
Disruptions of this tuning, even to a subtle 
extent, are likely to have negative functional 
consequences and could contribute to disease.
An open question is how communication 
to oligodendrocytes is produced by non- 
glutamatergic axons — for example, 
GABAergic axons — that are also myelinated 
but presumably lack the necessary machinery 
for vesicular glutamate release. Possibilities 
include an AMS that depends on other 
neurotransmitters native to those axons, 
non-vesicular release of glutamate (for 
example, reversal of glutamate transporters) 
or other transmitters such as ATP11; this 
important question is unresolved and 
deserves further study. A related point of 
interest is the heterogeneity of the AMS 
within the CNS. Single-cell RNA sequencing 
has described several mature oligodendrocyte 
populations that all express key NMDAR 
subunits but at differing levels79. Differential 
expression of NMDAR subunits might 
affect their function but also might alter the 
sensitivity of myelin to axonal glutamate.
Contribution to disease?
If communication between axons and 
myelin is important for normal physiology, 
disruption of this signalling may be 
responsible for a host of diseases adversely 
affecting not only white matter but also 
axon–oligodendrocyte interactions within 
the cortex. Both axonal and oligodendro-
glial processes are energy-consuming 
compartments and thus susceptible to 
metabolic challenges. Although neurons are 
rapidly injured in the absence of oxygen, the 
metabolic distress that (less acutely but dis-
proportionately) affects oligodendrocytes is 
the lack of glucose, because aerobic glycolysis 
is an important pathway of oligodendro glial 
ATP production2,80. Accordingly, elucidating 
the physiology of the AMS may lead to novel 
drug targets. Although highly speculative at 
this time, with evidence awaiting appropriate 
experimentation, we envision that AMS 
dysfunction contributes to various CNS 
disorders with white-matter involvement, 
especially in the earliest manifestations of 
pathology. Clinically important examples 
include, but may not be limited to, multiple 
sclerosis, ischaemia, neuropsychiatric 
disorders and AD, some of which are 
discussed below.
structure or on the axon directly or could 
act indirectly by impairment of the ability 
of the oligodendrocyte to provide metabolic 
support to its fibre. The AMS may be a 
locus for abnormal downstream effects of 
this excitotoxicity, including generation 
of antigenic proteins and lipids through 
excess activation of myelin-localized 
proteases and lipases, resulting in release 
of highly antigenic debris (FIG. 3). If true, 
then therapies designed to mitigate chronic 
axo-myelinic excitotoxicity could provide 
cytoprotection for both presynaptic and 
postsynaptic elements (the axon and the 
myelin, respectively), preserving functional 
integrity of vital myelinated tracts and, 
at the same time, suppressing secondary 
inflammatory damage by reducing the 
antigenic load presented to a dysregulated 
immune system. Thus, such cytoprotective 
strategies targeting the AMS, in concert 
with currently available anti- inflammatory 
therapies, could represent a novel approach 
for MS therapeutics, not only for early 
inflammatory relapsing-remitting disease 
but, perhaps more importantly, also for 
later-stage progressive MS, for which 
effective therapies are very limited.
Neurodevelopmental and psychiatric 
disorders. It is also plausible that a 
perturbation of AMS function contributes to 
psychiatric diseases, including schizophrenia, 
bipolar disorder and depression, that 
have frequently shown white-matter 
involvement87. A vital conduit for signalling 
between hemispheres, myelin-rich white 
matter constitutes nearly half of the 
volume of the human brain. Here, myelin 
determines the speed and temporal 
coherency of signalling, known to be crucial 
for higher brain functions. Alterations in 
spike-timing-dependent plasticity underlie 
observable changes in cognitive behaviours 
including attention and mood88. Whether 
myelin actively contributes to psychiatric 
disease or passively reacts to upstream 
neuronal injury and treatment remains 
controversial. Important evidence has 
emerged from unbiased genetic studies 
in post-mortem schizophrenic brains, 
identifying reductions in gene transcripts 
in myelin-forming oligodendroglia89. 
Several lines of radiological, genetic and 
clinical evidence implicate white matter, 
and, by extension, potentially the AMS, in 
schizophrenia. Neuroimaging studies reveal 
structural changes in the prefrontal white 
matter of patients with schizophrenia. A 
recent systematic study of diffusion tensor 
imaging in early-onset schizophrenia showed 
Multiple sclerosis. Multiple sclerosis (MS) 
is a chronic progressive disease of unknown 
aetiology, characterized by multifocal lesions 
of inflammatory demyelination exhibiting 
perivascular inflammation, complement 
deposition and other immune footprints. 
However, a subset of very early lesions can be 
devoid of substantial inflammation, instead 
exhibiting subtle myelin injury without 
overt demyelination and phagocytosis of 
myelin debris, oligodendrocyte apoptosis 
and microglial activation81,82. Such findings 
raise the possibility that at least in some 
cases, degenerative CNS pathology precedes 
inflammation83. Specifically, pathology 
at the inner tongue of myelin suggests 
that a perturbation of the AMS — with 
resulting biochemical alterations of myelin 
components, possibly impaired transfer 
of metabolites and likely other deleterious 
effects — plays a primary role in the 
evolution of MS lesions. Such lesions also 
accumulate electron-dense vesicles and 
axonal mitochondria, suggestive of local 
metabolic stress84. As might bepredicted 
for a dysfunctional interface between axon 
and myelin, the inner-tongue pathology 
in some cases of MS includes the loss 
of myelin-associated glycoprotein, an 
adaxonal cell adhesion protein, but not of 
MBP, which subserves myelin compaction. 
Structural perturbation of the most distal 
myelin compartment, that is, adjacent to its 
underlying axon, is one possible mechanism 
by which an oligodendrogliopathy could 
lead to disease. Here, we hypothesize 
that aberrant glutamatergic transmission 
represents a potential mechanism by 
which the AMS might contribute to MS 
pathogenesis. Although a causal relationship 
is far from established, it is noteworthy that 
MS genome-wide association studies have 
identified genes whose products are involved 
in glutamate homeostasis85. Whether 
glutamate excitotoxicity, shown to be an 
important component in relapsing-remitting 
MS86, acts via myelinic NMDARs or whether 
additional mechanisms involving activation 
of transient receptor potential (TRP) 
channels, as shown for hypoxic injury43, also 
contribute remains to be determined.
Although glutamatergic dysregulation in 
MS is still hypothetical, it is tempting 
to speculate that defective signalling, due to 
ongoing inflammation, a putative underlying 
degenerative process or both, establishes 
an environment of ‘chronic excitotoxicity’ 
with the axo-myelinic signalling machinery 
being a potentially key target. Chronic 
overstimulation of the axo-myelinic complex 
could have deleterious effects on myelin 
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consistent decreases in fractional anisotropy, 
a surrogate marker of white-matter 
integrity90. Animal models of dysmyelination 
that successfully phenocopy the disease91 
have strengthened the association between 
white-matter perturbations and the evolution 
of schizophrenia- like psychoses. Defects in 
Ca2+ handling and glutamate homeostasis 
were among patterns identified in a 
genome-wide association study92, which 
although highly speculative, raises the 
possibility that perturbed Ca2+ signalling 
via aberrant glutamate receptors at the 
Down syndrome suggest potential AMS 
involvement in this condition as well. 
Olmos-Serrano et al. described novel and 
robust abnormalities in gene expression 
associated with oligodendrocyte development 
and myelination94. Changes in callosal-fibre 
compound action potentials (a summation of 
individual axonal action potentials recorded 
by a surface electrode) in a mouse model of 
Down syndrome exhibited abnormalities in 
axonal firing rates and network synchronicity. 
Whether or not these abnormalities involve 
the AMS is not yet clear, but in support of 
AMS, in the context of known white-matter 
abnormalities in these patients, contributes 
to the disease. Lastly, the finding that 
transplanted OPCs derived from induced 
pluripotent stem cells from people with 
schizophrenia are impaired in their capacity 
to myelinate indicates cell-autonomous 
effects of the oligodendroglial lineage on the 
development of psychopathology93.
Regarding white-matter-driven effects on 
network synchronicity, recently described 
changes in white-matter processes at 
the cell, molecular and systems levels in 
Figure 3 | Proposed pathological consequences of overactivation of the 
axo-myelinic synapse. Overactivation of the axo-myelinic synpase (AMS) 
can potentially occur at multiple sites and can be acute, such as the global 
restriction of energy supply that occurs during acute ischaemia, or chronic, 
which may involve impairment of transmitter re-uptake or direct overstimu-
lation of myelinic NMDA receptors (NMDARs). White-matter ’energy failure’ 
would impair the ability of the oligodendrocyte to generate lactate for 
export to the axon, also impeding the ability of axonal mitochondria to syn-
thesize ATP (step 1). The reduction in axonal ATP results in failure of ion trans-
porters, which in turn causes pathological Na+ influx and K+ efflux with 
resultant depolarization of axons, activation of voltage-gated Ca2+ channels 
(Cav) (step 2) and excessive release of Ca
2+ from stores (step 3). This Ca2+ 
release not only directly injures the axon by overactivation of Ca2+-
dependent axonal enzymes but also stimulates excessive vesicular gluta-
mate release into the periaxonal space (step 4). In addition, pathological 
entry of Na+ into the axon together with loss of K+ promotes reversal of Na+-
dependent glutamate transporters (GluTs) and glycine transporters (GlyTs) 
(step 5), further exacerbating the increase of agonists at myelinic receptors. 
Excessive Ca2+ entry through these receptors over time, together with the 
inability of the myelin and/or oligodendrocyte to buffer these Ca2+ loads 
because of energy deprivation, could overactivate several key enzymatic 
pathways, leading to aberrant biochemical modification (indicated by 
dashed arrows) of myelin components (step 6). Ca2+-activated calpains and 
phospholipases will degrade myelin proteins and lipids, respectively, and if 
persistent and exceeding the capacity for repair, this will eventually lead to 
demyelination of the axon. Peptidylarginine deiminases (PADs) are Ca2+-
dependent enzymes that convert positively charged arginine residues on 
myelin basic protein (MBP) to citrulline. The deficit of positive charge on cit-
rullinated MBP (citMBP) could focally disrupt the compacted myelin 
sheath101 (step 7), promoting the release of antigenic citMBP and lipid debris 
(step 8). In a host predisposed to immune-system overactivation, a T cell-
driven adaptive immune response — together with other immune effectors 
such as macrophages and microglia (not shown) — could result in a second-
ary wave of inflammatory pathology and autoimmune attack, causing further 
damage to myelin and the axon (step 9). We propose that such a scenario 
may underpin the intertwined degenerative and autoimmune pathogenesis 
of multiple sclerosis. RyR, ryanodine receptor. Adapted with permission from 
REF. 6, Elsevier.
T cell
Lipids
citMBP
Oligodendrocyte
Nature Reviews | Neuroscience
2
1
3
4
5
6
7
8
9
Axoplasmic reticulum
Mitochondrion
NMDAR
Cav
RyR
GluTAxon
Periaxonal space
GlyT
ATP
Glutamate
Glycine
Na+
K+
• Calpains
• Phospholipases
• PADs
Autoimmune
attack
citMBP
Myelin
Ca2+
Cl–
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this notion, there is mounting evidence of 
primary white-matter alterations and their 
profound effects on network synchronicity.
Neurodegenerative disorders. Advanced 
age is the single most important risk factor 
for sporadic AD. When the brains of very 
old non-human primates are studied by 
electron microscopy, cortical oligodendro-
cytes and myelinated fibres exhibit the 
most visible ultrastructural defects95. These 
include myelin outfoldings, delamination, 
vacuolization, axonal swellings and 
degeneration and secondary inflammation, 
all features that are likely to interfere with 
normal AMS downstream signalling and 
metabolic coupling. AD is chiefly viewed as 
a grey-matter disorder thought to be caused 
by the neurotoxic accumulation ofβ-amyloid 
and tau proteins. However, evidence 
increasingly points to a role for white-matter 
abnormalities in disease pathogenesis. This 
includes the analysis of both human AD 
tissue and relevant animal models indicating 
that defective axonal transport precedes 
amyloid accumulation and subsequent 
grey-matter pathology96. Similarly to in 
schizophrenia, imaging of patients with 
mild cognitive impairment, a condition that 
often leads to AD, reveals that white-matter 
damage may not only be independent of 
grey-matter atrophy but may precede it97.
Interestingly, AD-related amyloid-β (Aβ) 
peptides increase activity of NMDARs98, 
which are known to also associate with 
the AMS, as discussed above6. Thus, Aβ 
could promote a chronic glutamatergic 
overstimulation of the oligo dendroglial 
compartment. We note that glutamatergic 
tone is also regulated, at least in part, 
through copper-bound major prion protein 
(PRP). PRP diminishes the affinity of the 
co-agonist glycine at the NMDAR, which 
would reduce Ca2+ fluxes through these 
receptors (including those present in 
myelin). Given that Aβ binds copper with 
high affinity, this could independently 
lead to a copper dysregulation at the AMS, 
chronic excitotoxicity and ultimately myelin 
pathology, with similar consequences for 
axonal integrity as described above for 
MS but without the added autoimmune 
inflammatory component. Finally, Aβ 
oligomers can directly bind PRP99, resulting 
in dysregulation of NMDAR kinetics98 and 
potentially chronic excitotoxicity at the AMS. 
Taken together, the known pathological 
properties of Aβ and the emerging molecular 
architecture of the AMS suggest that an 
important component of AD pathology may 
include primary white-matter degeneration.
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If AMS dysregulation plays a role 
in white-matter disorders, therapeutic 
design will require particular attention to 
the space that needs to be accessed. Drugs 
would need not only to cross the blood–
brain barrier but also to enter the restricted 
periaxonal space, the presumed location of 
the AMS. Small molecules below ≈2 kDa can 
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myelin sheath was already compromised.
Conclusion
Communication via vesicular release of 
neurotransmitter is the main mode of 
intercellular transmission in the CNS. In 
much the same way that neuro transmitter 
release at neuronal synapses allows 
communication between neurons, recent 
evidence now indicates that axons release 
transmitters along their internodes to signal 
the overlying myelin sheath, forming the 
basis of what we refer to as the AMS. This 
novel signalling arrangement could support 
activity-dependent metabolic coupling 
between the axon and its overlying myelin 
sheath. Moreover, by facilitating metabolic 
support of axons from their myelinating glia, 
fine-tuning of developmental myelination 
and later of mature myelin nanostructure, 
and other potentially important homeostatic 
functions yet to be discovered, such chemical 
communication between axons and oligo-
dendrocytes and/or myelin may have major 
implications for the physiological operation 
of the CNS. Perturbations of this fundamental 
new mode of intercellular signalling could 
underpin a number of important CNS 
diseases in which disruption of myelin and 
white matter are key pathophysiological 
events;in turn, pharmacologically targeting 
the AMS may represent a new direction 
for a number of important CNS disorders 
currently resistant to therapeutic efforts.
Ileana Micu, Jason R. Plemel, Andrew V. Caprariello 
and Peter K. Stys are at the University of Calgary, 
Cumming School of Medicine, Department of Clinical 
Neurosciences, 3330 Hospital Drive NW, 
Calgary, AB T2N 4N1, Canada.
Klaus-Armin Nave is at the Department of 
Neurogenetics, Max Planck Institute for Experimental 
Medicine, 37075 Göttingen, Germany.
Correspondence to P.K.S.  
pstys@ucalgary.ca
I.M., J.R.P. and A.V.C. contributed equally 
to the manuscript.
doi:10.1038/nrn.2017.128 
Published online 9 Nov 2017
Corrected Online 14 Dec 2017
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Acknowledgements
Work in the authors’ laboratories was supported by the 
Deutsche Forschungsgemeinschaft (Centre for Nanoscale 
Microscopy and Molecular Physiology of the Brain) and an 
European Research Council (ERC) Advanced Grant (to K.A.N.) 
and by the Multiple Sclerosis Society of Canada, Canadian 
Institutes of Health Research, Alberta Innovates — Health 
Solutions, Alberta Prion Research Institute, Canada Research 
Chairs and the Canada Foundation for Innovation (to P.K.S.).
Author contributions
P. K. Stys: researching data for article, substantial contribution 
to discussion of content, writing, review/editing of manuscript 
before submission. I. Micu: researching data for article, sub-
stantial contribution to discussion of content, writing, review/
editing of manuscript before submission. J. R. Plemel: 
researching data for article, substantial contribution to discus-
sion of content, writing, review/editing of manuscript before 
submission. A. V. Caprariello: researching data for article, 
substantial contribution to discussion of content, writing, 
review/editing of manuscript before submission. K.-A. Nave: 
substantial contribution to discussion of content, writing, 
review/editing of manuscript before submission.
Competing interests statement
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional 
claims in published maps and institutional affiliations.
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PERSPECT IVES
NATURE REVIEWS | NEUROSCIENCE VOLUME 19 | JANUARY 2018 | 57
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CORRIGENDUM
The nano-architecture of the axonal cytoskeleton
Christophe Leterrier, Pankaj Dubey & Subhojit Roy
Nature Reviews Neuroscience 18, 713-726 (2017)
In Box 1 of this article, the sentence “Actin filaments are approximately 8 nm in diameter, are composed of heterodimers 
of α-actin and β-actin (known as G-actin) and require ATP for polymerization” should have read “Actin filaments are 
approximately 8 nm in diameter, are composed of actin monomers (known as G-actin) and require ATP for polymerization”. 
The article has been corrected in the online version.
PERSPECT IVES
58 | JANUARY 2018 | VOLUME 19 www.nature.com/nrn
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reserved. ©
 
2017
 
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part
 
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Nature.
 
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ri ghts
 
reserved.
	Abstract | It is widely recognized that myelination of axons greatly enhances the speed of signal transmission. An exciting new finding is the dynamic communication between axons and their myelin-forming oligodendrocytes, including activity-dependent sign
	Development of axo-myelinic coupling
	Figure 1 | Molecular architecture of the proposed axo-myelinic synapse. Depolarization of the internodal axolemma by traversing action potentials (step 1) is detected by voltage-gated Ca2+ channels (Cav) (step 2). Because of the insulating properties of t
	Molecular physiology
	Figure 2 | Hypothetical transition from OPC synapse to axo-myelinic synapse. Left: In oligodendrocyte progenitor cells (OPCs), axonal activity can be monitored via synaptic communication. In pre-myelinated axons, the arrival of an action potential results
	Functions of the axo-myelinic synapse
	Contribution to disease?
	Figure 3 | Proposed pathological consequences of overactivation of the axo-myelinic synapse. Overactivation of the axo-myelinic synpase (AMS) can potentially occur at multiple sites and can be acute, such as the global restriction of energy supply that oc
	Conclusion