This Is MS Multiple Sclerosis Knowledge & Support Community

A recent study shed some more light on the cell molecular processes of central nervous system, and gave me an excuse to bump this thread up. Quote from the abstract:

• "It is generally believed that fast transmitter release is restricted to nerve terminals that contact postsynaptic cells in the gray matter. Here we show in the rat brain that the neurotransmitter glutamate is also released at discrete sites along axons in white matter in the absence of neurons and nerve terminals."

I think that the discovery of axons producing glutamate also in white matter could be important because

• glutamate overdose is found to be able to cause cell death in central nervous system.
• it could partly explain changes seen in white matter in MS.
• some drugs with neuroprotective potential - like minocycline - can inhibit the toxicity produced by glutamate.
• any study that challenges current understanding may create progress in neurosciences in the long run.

And now the fun part, layman's speculation. I'd like to underline that I don't have any scientific background to tell what is possible and what is not, which makes it really easy to think differently. Anyway, if MS was primarily a neurodegerative disease that starts with changes in gray matter, I suppose one could assume that

• since axons in white matter are extensions of those in gray matter, negative changes in gray matter might make them produce too much glutamate in white matter.
• central nervous system might even try to compensate weakened connectivity caused by axonal degeneration with producing more neurotransmitter glutamate.
• too much glutamate might be able to kill oligodendrocytes (myelin making cells), and maybe the cell death could cause inflammation seen in white matter lesions.
• a relapse in RRMS might be caused by temporary overproduction of glutamate followed by death of oligodendrocytes and/or inflammation in white matter. And maybe a remission occurs only if central nervous system is able to rewire or reorganize itself (in fMRI studies it has been shown that performing even a simple task requires more activity in MS brain than in healthy brain).

In any case, it is an interesting study. Here's another quote from the article:

• "On the other hand, under pathological conditions the widespread release of glutamate along axon tracts might be harmful: axonal transmitter release is likely to contribute to the ability ofNMDA receptors to mediate ischemic damage of mature oligodendrocytes. Therefore, drugs that modulate transmitter release in white matter might be promising therapeutic targets.
  
  Axonal transmitter release might also challenge the concept of exclusively directed signal spread in neuronal networks of the CNS. As the axons in white matter are simply elongations of axons in gray matter, it seems likely that extrasynaptic transmitter release also occurs along intracortical axons and that this activates neurons that are not synaptically connected. The resulting spread of neuronal signals would strongly increase the apparent connectivity of neural circuits and could have a significant impact on information processing in the brain."

Any comments?

Be well.

-finn

Hi there Finn,

As one layman to another, your "speculation" makes absolutely perfect sense. I agree with everything you said.
A couple of questions arise, however, in this picture of white and grey matter which is a new way of looking at things for me: if the white matter is only a part of an axon, why is that? Why does an axon need to be myelinated along just a part of its length? Also, couldn't this hint at a different role for myelin -- if axons are releasing neurotransmitters along their length, and stimulating their neighbours without using a synapse, could myelin function as a shield against overstimulation and confusion in certain areas?

Just a thought,

Dom.

Hi Dom,

and thanks for your post. Let the gathering of laymen continue:

TwistedHelix wrote:if the white matter is only a part of an axon, why is that? Why does an axon need to be myelinated along just a part of its length?

I'm not sure if I have got it right, but I think that myelinated axons go through the white matter, and there is myelin around them also in other parts of central nervous system, even in the gray matter. And in MS researchers have already found demyelination in the gray matter, too.

TwistedHelix wrote:if axons are releasing neurotransmitters along their length, and stimulating their neighbours without using a synapse, could myelin function as a shield against overstimulation and confusion in certain areas?

Good question. I guess it could. On the other hand, maybe sometimes axons release more neurotransmitters than necessary when trying to make sure that the message gets through in an injured nervous system. And maybe that could explain the overactivity of MS brain seen in fMRI scans.

Be well.

-finn

finn wrote:I'm not sure if I have got it right, but I think that myelinated axons go through the white matter, and there is myelin around them also in other parts of central nervous system, even in the gray matter.

Hi Finn,
I'm not sure that I'm 100% correct in this but I've read that the myelin is a fatty substance, whitish in color and it's abundance is the source of the name "white matter". Using that little bit of knowledge I'd have to guess that the density of myelin wrapped axons/neurons/nerve fibers is just less in the gray matter.

Bob

Lyon,

Lyon wrote: I've read that the myelin is a fatty substance, whitish in color and it's abundance is the source of the name "white matter". Using that little bit of knowledge I'd have to guess that the density of myelin wrapped axons/neurons/nerve fibers is just less in the gray matter.

Yes, I agree with you. As far as I have understood white matter is mostly myelin, but I'd say the amount of myelin is much smaller in the gray matter.

Anyway, it's probably safe to say that white matter transmits information and grey matter processes it.

-finn

finn wrote:Anyway, it's probably safe to say that white matter transmits information and grey matter processes it.

Hi finn,
Again, I'm not an expert and my point isn't to nitpick because I understand what you're saying and I think I generally agree but for the sake of accuracy doesn't it all involve tranmission?

Or maybe it's better to say that effective transmission is essential in either regard?
Bob

Lyon wrote:my point isn't to nitpick because I understand what you're saying and I think I generally agree but for the sake of accuracy doesn't it all involve tranmission?

Well, maybe it can't be called nitpicking, but definitely thread hijacking ;-)

Or did you have something to comment on the subject?

-finn

finn wrote:Or did you have something to comment on the subject?

Man, you Finns really get to the point, don't you?

No, no comment.

Like you, I read it and was left with no idea what it all meant or if it even relates to the MS process ;)

Bob

Bob,

Lyon wrote: Man, you Finns really get to the point, don't you?

Well, we tend to be quite straightforward people. To tell you the truth, sometimes it might even cause some problems when communicating with the rest of the world.

Lyon wrote:Like you, I read it and was left with no idea what it all meant or if it even relates to the MS process ;)

Yeah, but it was nice reading, wasn't it?

Seriously, like I wrote earlier, the discovery of glutamate production also in the white matter might be able to explain many things related to the pathology of MS.

-finn

I must admit to a bit of confusion here: it has always been my understanding that there is no myelin in the grey matter; this from Wikipedia:

"Grey matter is composed of unmyelinated neurons as opposed to white matter (myelinated neurons). It has a grey brown color which comes from the capillary blood vessels and the neuronal cell bodies"

So the item you linked to, Finn, which mentioned demyelination in grey matter, seems to contradict this.

The discovery that neurons release transmitters along their length paints a revolutionary picture of brain activity: previously, they had only been thought to communicate at the synapse but now it appears the brain is flooded with neurotransmitters. That's what I meant by suggesting a new role for myelin -- that it keeps out this deluge to keep the signal carrying pure, and keeps in the transmitters which are released by the neuron in order to boost the signal it is carrying. After all, in the grey matter it would be ideal for the dendrites and cell bodies to be suffused with neurotransmitters because this would be just the right environment for information processing, complex thought, and the vagaries of emotion, whereas in the white matter neurons carrying sensory and motor signals would need to keep their information "clean". Overproduction of Glutamate to compensate for damage is a good candidate for continuing the cycle of destruction, though we still don't know how it begins,

Dom.

Dom,

in situations like this I really wish I had even some solid knowledge on neurobiology (and maybe a microscope, a scalpel, and a brain in a dish...). On the other hand, occasionally it seems like professionals don't know that much for sure about what's really happening in the central nervous system, either. I suppose they found small amounts of myelin in the gray matter for the first time only a couple of years ago, and the study of demyelination in the gray matter in MS brain was dated january this year. "The times they are a-changin'", hopefully fast.

TwistedHelix wrote:The discovery that neurons release transmitters along their length paints a revolutionary picture of brain activity: previously, they had only been thought to communicate at the synapse but now it appears the brain is flooded with neurotransmitters. That's what I meant by suggesting a new role for myelin -- that it keeps out this deluge to keep the signal carrying pure, and keeps in the transmitters which are released by the neuron in order to boost the signal it is carrying.

Good thinking. Myelin is supposed to be there to protect axons, but maybe it also protects, boosts, and supports neurotransmitters in order to keep the signal pure. I like the idea.

But what if more than being a linear process, signalling would be based on a matrix like structure (broken English, sorry. I hope you'll get what I mean)? Then, if there was something wrong with the primary route for the signal, the axon might try to find alternative routes by spreading more neurotransmitter around itself in the area where the problem occured. That could explain both lesions with dead oligodendrocytes, and the imaging finding that performing similar tasks occupies MS brain more than healthy brain.

TwistedHelix wrote:After all, in the grey matter it would be ideal for the dendrites and cell bodies to be suffused with neurotransmitters because this would be just the right environment for information processing, complex thought, and the vagaries of emotion, whereas in the white matter neurons carrying sensory and motor signals would need to keep their information "clean".

Couldn't agree more. Processing thoughts, emotions, senses and movement at the same time surely takes all available neurotransmitters.

TwistedHelix wrote:Overproduction of Glutamate to compensate for damage is a good candidate for continuing the cycle of destruction, though we still don't know how it begins.

Yes, like a drugdealer said to another in a brilliant TV-series, "true that". I'd say one big problem is that the idea is more or less against the concensus opinion. Instead of demyelination, the first pathological event would be some kind of damage in neurons or axons.

Be well.

-finn

I’ve got a few comments. The first is I totally agree with Dom’s initial comment--
Dom wrote:

As one layman to another, your "speculation" makes absolutely perfect sense. I agree with everything you said.

Finn wrote:

Instead of demyelination, the first pathological event would be some kind of damage in neurons or axons.

I definitely think this is entirely possible (maybe even probable). There’s certainly research indicating damage to both gray matter and axons happens early in the disease course.

I think Bromley originally posted this info about early gray matter involvement.

Gray Matter Damage in MS

a primarily GM-related process may be the earliest manifestation of MS

There’s also info about early axonal damage. Axonal Injury in Early MS

Irreversible brain damage associated with axonal dysfunction occurs at a very early stage in patients with clinically isolated syndromes

So, it seems to me that the first pathological events could indeed be some kind of damage in neurons or axons instead of the myelin. And, this new information you posted about axons producing glutamate is consistent with and seems to complement research Dunmann posted last year.

Unraveling Brain Damage in MS

The researchers showed myelin contains specialized receptors for glutamate
They discovered the surface of myelin has tiny open pores that provide a gateway for calcium to enter. If too much calcium enters, it can injure the myelin and affect our ability to walk, talk or see.

So, I would think these recently discovered pores in myelin present an opportunity for the glutamate produced by axons to exit and damage the myelin just as easily as they provide a gateway for glutamate to enter the myelin and damage axons, i.e., the pores on the surface of myelin provide a portal for the glutamate to go in either direction and cause damage and then the inflammation.

It’s definitely consistent with your speculation Finn where you wrote:

too much glutamate might be able to kill oligodendrocytes (myelin making cells),

and, to take it one step further, Dom wrote:

Overproduction of Glutamate to compensate for damage is a good candidate for continuing the cycle of destruction,

If I understand it correctly this would be something of a neuroprotective response, and when that fails and the myelin is damaged, inflammation follows in an attempt at remyelination(another neuroprotective response). Anyway it's my current understanding inflammation is needed for remyelination.

I think the plausibility of this sequence of events (neuronal and axonal damage initiate the process) is all reinforced by the research that men have thicker myelin and fewer lesions than women but a tendency for more severe disease progression. Could it be that it takes longer for the glutamate from axons to chew threw that thicker myelin men have and finally bring on the inflammation to try and repair it?

There’s also other MRI data that suggests an “inside out” initiation of pathology in MS. On slide 45 of this presentation Advanced Techniques in MRI Daniel Pelletier notes:

MTR changes in normal appearing white matter (NAWM) precede the appearance of new enhancing and T2 lesions—a challenging concept.

Finn—it’s just possible you found and developed an explanation for this challenging concept. Challenging it is, but the times they are a changin’

Dom wrote:

Overproduction of Glutamate to compensate for damage is a good candidate for continuing the cycle of destruction, though we still don't know how it begins

Did you miss that the stress hormone cortisol causes glutamate toxicity? Of course I think there are a lot of things that cause glutamate toxicity. Cortisol could be one of them though.

May the gathering of speculators carry on....I don't have a shred of scientific background either.

Take care all

Sharon

I've been trying to educate myself about glutamate excitotoxicity, and it's very, VERY complicated! First, it came as a bit of a surprise to discover that it may possibly be a normal mechanism used in brain development: I think they're talking about brain plasticity. When we are babies learning to balance building blocks, and maybe even later on in life learning a new sport or skill, certain circuits are reinforced while the ones which are not used die. I'd always assumed they die out through lack of use, but it seems as if those that are over-sensitive are actually killed off through excitotoxicity, (after all, I suppose an overactive circuit is as detrimental as an underactive one). It's always the posts synaptic dendrite which dies .

As far as I can tell, glutamate excitotoxicity is currently regarded as being common to a large number of neurological conditions -- it is seen as the final consequence of a whole host of different circumstances, and it is these circumstances which determine the nature of the illness or condition you have. For instance multiple sclerosis, stroke and ischaemia, Parkinson's, Huntington's, ALS, Alzheimer's and direct physical injury all terminate in this process.
Dietary intake of monosodium glutamate, hydrolysed vegetable protein or aspartame are synergistic, (in other words, sub-toxic intake of more than one can still lead to toxic amounts), and can all raise glutamate. Normally, they will raise serum levels but not brain levels, however, I can't help wondering what would happen if you had a leaky BBB......?

The actual cause of death in glutamate excitotoxicity is calcium overload, but it's not simple: a cascade of events is unleashed which just makes things worse -- a whole host of enzymes is released like phospholipase A, which generates platelet activating factor, which activates the release of more glutamate. Also arachidonic acid, which prevents the reuptake of glutamate, thereby exacerbating the stimulation of glutamate receptors, which then go on to release more arachidonic acid. This acid also forms oxygen free radicals, which activate phospholipase A... round and round...

Conditions like hypoxia and neurodegenerative disorders also reduce levels of ATP, which is used to transport calcium and power the sodium potassium pump and therefore affects the sodium gradient, (the difference between one side of a membrane and the other), this gradient is crucial for the antiporter, which shifts excess calcium out of a neuron.
Did I say complicated? This is just the start!! My head is spinning, so I'm going to go now and watch some children's TV -- I need to learn some SHORT words for a change!

Dom.

I would like to add some information for this topic.

Myelin was 'invented' not for axonal insulation, axon is not a wire, the main purpose - increase the speed of the impulse. Also it serves for signal speed modification purpose. Thickness and gaps (their number and intervals between them) are not constant, they vary during the lifetime of axon-myelin complex.

Myelin damage is primary for MS, axons survive up to 8-10 years (all terms approximate of course, just watch the scale)
Myelin damage could be reversible if treated in first hours, say like a stroke. If MS patients could get this help when they need it most, the damage will be minimal.
(It was somewhere on the net last year, a letter from the MS patient from New Zealand - he waited for neurologist consultation ONE MONTH since first symptoms of relapse appeared!)

Myelin is present in whole nerve system where is a demand for selective increase of the signal, times really matter, imagine for ex. walking, to keep it functional a lot of different neurons (not from one local point) must fire the set of signals to create an ansemble/array for this particlular movement. Slight delay of one signal may couse the interraption of the moving pattern, etc.

Myelin in gray matter was forever, I think it was seen from the beginning of the 19th century.

There are at least more than 30 neurotransmitters in the brain, all of equal (more or less) importance. That why attempts to modify the quantity (via different mechanisms) of single one will lead to failure to control the whole complex (for ex. depression drugs).
U can think about neurotransmitters as an analogic way of operations, compare the synaptic way as a digital one, of course it is more complex

Matrix scheme of operation of the brain was proven many years ago. We memorize this way.

Any medication which interferes the inflammatory cycle will have influence on MS.

Functional (normal) demyelinization/remyelinization is a part of brain development and plastisity, we are who we are as a result of this process. Any drug who alters this process (de-/re-myelinization) will have long -term impact on the brain function.

As an any other living organ contant changes in brain are natural, of course the brain has a bunch of tools for removing old/damaged parts and for reconfiguration of the stucture on demand.

It is pretty difficult to do something with the brain using one single drug because of enormous variety of receptors, complexity of interactions, etc.

More grugs on the market - more tools we have to work with. U can't fix Bentley with bicycle wrench only. Most important thing in using medications - it's PROPER use.

Sorry, the subject is HUGE, can't cover everything.

Kind regards,
Tony

Sharon,
thank you for sharing your thoughts. Very interesting post!

Shayk wrote:I definitely think this is entirely possible (maybe even probable). There’s certainly research indicating damage to both gray matter and axons happens early in the disease course.
---- clip ----
So, it seems to me that the first pathological events could indeed be some kind of damage in neurons or axons instead of the myelin. And, this new information you posted about axons producing glutamate is consistent with and seems to complement research Dunmann posted last year.
---- clip ----
So, I would think these recently discovered pores in myelin present an opportunity for the glutamate produced by axons to exit and damage the myelin just as easily as they provide a gateway for glutamate to enter the myelin and damage axons, i.e., the pores on the surface of myelin provide a portal for the glutamate to go in either direction and cause damage and then the inflammation.

I appreciate you reposting those links. Good stuff. It was you who originally posted the "inside out" vs. "outside in" study here a while ago, wasn't it? It showed that axonal degeneration could cause demyelination in an animal model, and it wouldn't always have to be the other way around. I remember being very impressed by it.

Shayk wrote:when ... the myelin is damaged, inflammation follows in an attempt at remyelination.

Somebody wrote somewhere that "any tissue damage is followed by inflammation". To me it makes much more sense than thinking that the whole destructive process in MS would start with inflammation. As it has already been suggested, inflammation may have many beneficial properties in MS, and demyelination caused by it can only be concidered as "collateral damage".

Shayk wrote:Anyway it's my current understanding inflammation is needed for remyelination.

It might be safer to only state that inflammation creates beneficial circumstances for remyelination ;-)

Shayk wrote:I think the plausibility of this sequence of events (neuronal and axonal damage initiate the process) is all reinforced by the research that men have thicker myelin and fewer lesions than women but a tendency for more severe disease progression. Could it be that it takes longer for the glutamate from axons to chew threw that thicker myelin men have and finally bring on the inflammation to try and repair it?

Yes, I personally think it could. On the other hand, maybe those with more severe disease progression just suffer more neurodegeneration than demyelination? After all, "inflammation defines disease course". Demyelination and remyelination (reverseable disability) have been linked to inflammation, but axonal/neuronal degeneration (permanent disability) hasn't. It looks like the more inflammation, the less permanent disability.

Shayk wrote:Did you miss that the stress hormone cortisol causes glutamate toxicity? Of course I think there are a lot of things that cause glutamate toxicity. Cortisol could be one of them though.

You brought up an interesting issue. I agree with you, "natural elements" such as stress (and hormones, nutrition, etc.) may have a huge effect on the disease onset and proression. As you have stated here several times, somebody ought to study them more.


Dom,
you have really dug deep, haven't you? I'm sure I'm not the only one who appreciates your ability to explain very complicated issues in an understandable manner. Are you sure you don't happen to have a doctoral degree in neurobiology?

Anyway, speculation is much easier when you only have the ability to think and operate on a level of simplified information, like I have :-)


Tony,
thanks for clarifying this stuff for us laymen. A couple of comments, though:

TonyJegs wrote:Myelin damage is primary for MS, axons survive up to 8-10 years (all terms approximate of course, just watch the scale)

I hope you don't mind me asking, but did you mean that the first pathological event in MS would be myelin damage?

TonyJegs wrote:Myelin in gray matter was forever, I think it was seen from the beginning of the 19th century.

Thanks, I needed that ;-)

TonyJegs wrote:Any medication which interferes the inflammatory cycle will have influence on MS.

Did you mean influence on symptoms or long term progression of the disease? If you meant progression, there seems to be also other opinions out there.

TonyJegs wrote:Functional (normal) demyelinization/remyelinization is a part of brain development and plastisity, we are who we are as a result of this process.

Yes, this makes a lot of sense.

Be well.

-finn