What would happen if you suddenly lost 10% of all synapses in the body?

chillier

chillier

Senior Member (Voting Rights)
As a lot of the genetic evidence points towards synapses, one very simple hypothesis is a general and randomised loss of synapses throughout the nervous system.

I want to vent a few disorganised thoughts and questions I have about that here. Tell me if it sounds implausible.

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Synapses are extremely dynamic as we know, and huge numbers of them are probably getting pruned and reinforced every night as you sleep. I understand there are also big pruning events that happen as a part of development such as during adolescence. What if though a one off event like a big infection or trauma leads to a single sudden loss of synapses in a relatively random way that is difficult to recover homeostatically?

What symptoms would you expect if 5% of synapses suddenly vanished, or 0.01,1,10, 20, 50, 90% etc of synapses vanished? The really key bodily functions probably have a lot of redundancy in terms of both numbers of neurons and synapses serving those functions so I imagine you'll stay alive at lower percentages.

Maybe if this synapse loss event happens to hit brain areas that are themselves responsible for processes involving synapse maintenance (eg sleep centers) it becomes harder to recover and you develop long term illness.

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A concept I think is interesting is sensitivity scaling of neurons and synapses - That a neuron in the long run likes to maintain a homeostatic firing rate. So if input is lost due to missing synapses the neurons could sensitise and fire when it isn't 'supposed' to - leading to for example erroneous reporting of peripheral fatigue states.

Something else I'm curious about is why in a disease like Multiple Sclerosis - where you get brain lesions I think in many different places but with some biases - you mostly get negative symptoms like fatigue, numbness, blindness, difficulty moving and so on, but less in the way of hallucinations or hearing voices that you might find in schizophrenia.

ME/CFS seems to be genetically closer to schizophrenia than MS but I'd still say the symptom profile of ME/CFS is closer to MS than schizophrenia.

What if in ME/CFS instead of taking chunks of CNS neurons offline from many possible different sites like in MS, you are instead randomly taking chunks of synapses offline, driven by the over firing of neurons that have been sensitised by previous rounds of synapse loss.

Is there a possibility that neurons like the eccentric medium spiny neuron have come up in cell type analyses simply for the reason that they have lots of synapses, and are particularly sensitive to changes in the make up of their synaptic inputs?
 
Good first point from @V.R.T.

Some other initial thoughts…

Would we see the commonality in symptoms if it were random?

Would symptoms look more like aging or other conditions of general low scale loss?

Would this be noticeable or measurable in brain scans or autopsy?

I suppose if we’re talking synapses then it could impact areas particularly sensitive to change or as you say without redundancy more than others. I’d expect it to impair more widely though and not have the sort of fluctuations of function but also recovery of say cognitive or intellectual function I experience and have heard others describe though. Unless there’s a process of loss and recovery? Maybe a maintenance problem whereby a normal recycling process fails for a period?

I will ponder more on this. Interesting idea to explore even if it doesn’t immediately feel right.
 
chillier said:
New synapses are made in the brain all the time so this is not a problem
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Oh then that makes this quite an interesting hypothesis. It would fit somewhat with many symptoms that are hard to explain or elucidate. Including the horrendous (probably) CNS symptoms I was having last night. It often feels like information is not travelling from brain to limbs and digits properly.
 
Something that I think would be necessary for a random loss of synapses to be causative, is whilst it seems to heuristically explain parts of the illness presentation quite well, you also generally have some fairly consistent symptoms like (muscle) pain. So somehow even this random loss has to invoke this rather specific symptom, at least in a substantial proportion of cases.

I would think that there are some neurogenerative conditions where there is fairly widespread loss of synapses without pain (perhaps many forms of Dementia or Schizophrenia), so you somehow either have to invoke that this loss is random in some specific domain, for example by effecting synapses that are somehow involved in some pain processes or such or somehow invoke a second process.
 
chillier said:
New synapses are made in the brain all the time so this is not a problem
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Why would the loss of synapses be a problem then?

I like @hotblack's idea:
hotblack said:
Unless there’s a process of loss and recovery? Maybe a maintenance problem whereby a normal recycling process fails for a period?
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What if the signalling to make new synapses to replace the ones lost during the infection is off? And when people improve/recover, that signalling is either gradually or suddenly fixed?
 
There are lots of situations where you probably effectively lose 10% of synapses suddenly - brain hypoxia during cardiac arrest or complicated anaesthesia, severe febrile delirium, acute alcohol poisoning (stag night), ECT, etc. The most obvious clinical feature is loss of memory, mostly short term but also long term episodic memory and sometimes procedural memory.
 
Evergreen said:
Why would the loss of synapses be a problem then?
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The analogy could be something along the lines of wildfires destroying trees. Sure new trees can grow but in the meantime we've just released a load of CO2 into the atmosphere making more wildfires even more likely. Unless we can grow the trees back and recapture the CO2 quickly enough then we're stuck.

In synapse terms maybe if you have too dramatic a drop off you've now destabilised the whole system, and the input loss is sensitising neurons making you more prone to a new synapse loss event. I appreciate this all might sound a bit hand wavy but I think somewhere in the dynamics of neuron and synapse sensitivity scaling is the possibility for wild fluctuations to occur.
 
V.R.T. said:
DRG T cells or T like cells somewhere?
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Glia, which are the brain's immune cells, which respond to immune signalling from the body's other immune systems. They aren't all exactly the same, so for a given cytokine, the glia in different parts of the brain would respond differently, and it would be different for each individual. I suppose the neuron responses to glia would differ as well.
 
Chandelier said:

Conclusions​

A 62 EV-miRNA signature provides insight into the interconnected neuro-systemic pathways disrupted in ME/CFS, particularly those governing neuronal connectivity and cellular scaffolding.
Within this candidate EV-miRNA signature, the top-ranked miRNAs—miR-21-5p, let-7f-5p, miR-26b-5p, and miR-20a-5p—emerge as potential candidate biomarkers whose specific elevation was not shared by HC.
These findings establish a valuable framework for targeted diagnosis and enhance our understanding of the molecular pathways involved in synaptic and structural alterations in ME/CFS
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New small study, maybe of relevance to this discussion.
 
one thing that's become apparent from having multiple people in my life with MS is that the heterogeneity of disease presentation really does come down to heterogeneity in which brain regions become affected. One person loses tactile sensation in a limb, another developed vision issues, another noticed a new difficulty in language processing (fatigue being the main exception here). This makes sense with a lesion affecting a large proportion of neurons in a specific area, with the focal point of that damaged area being stochastically determined (as far as we know). In some cases you can even see a very clear correlation between the severity of the symptom and the size of a particular lesion on an MRI changing over time.

If what you're proposing is a global randomness, I think it gets harder to explain symptoms. It seems very common for pwME to have impairment that drastically changes day to day, maybe even hour to hour. Synapses do reorganize over a time frame, but it would have to be a coordinated reorganization across pretty much an entire brain region to explain someone being able to speedily do a crossword in the morning and then struggle to comprehend text on their phone a few hours later. Or having a consistent trend of being able to walk to the store one day and then barely being able to make it to the bathroom during PEM the next day. Across multiple brain regions, really, since these are all complex tasks.
 
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jnmaciuch said:
If what you're proposing is a global randomness, I think it gets harder to explain symptoms. It seems very common for pwME to have impairment that drastically changes day to day, maybe even hour to hour. Synapses do reorganize over a time frame, but it would have to be a coordinated reorganization across pretty much an entire brain region to explain someone being able to speedily do a crossword in the morning and then struggle to comprehend text on their phone a few hours later. Or having a consistent trend of being able to walk to the store one day and then barely being able to make it to the bathroom during PEM the next day. Across multiple brain regions, really, since these are all complex tasks.
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Global randomness is not the same as an even distribution of synapse loss. Randomness produces patches and blotches at every order of magnitude, so I think it could look similar to the case with MS - but much more patchy perhaps.

The example you give about being able to speedily do a crossword in the morning and it become a garbled mess a few hours later could be explained by redundancy of functions of sets of neurons. Imagine for a normal person different neuron sets are being used and tire out and pass the baton to other neuron sets to create a consistent ability to do crosswords all day long. In an ME person you've got some neurons that are up to the task but once they're tire out you're done for until they rest up a bit.
 
chillier said:
In an ME person you've got some neurons that are up to the task but once they're tire out you're done for until they rest up a bit.
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Another thing that people describe is that they might be able to power through on an "adrenaline rush." That seems to align more with an intracellular issue in neurons, something that could be overcome with sufficient external signals, rather than a more structural issue affecting the coordination between neurons.
chillier said:
Randomness produces patches and blotches at every order of magnitude, so I think it could look similar to the case with MS - but much more patchy perhaps.
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I see your point, though the temporal dynamics are still quite different. What I observe in MS is a series of localized issues with onset correlating with lesion appearance, and which generally tend to stay bad until steroids are administered and a few days pass. If there's been permanent damage then the symptom is pretty constant for a much longer timeframe. The main thing that has ME/CFS-like temporal dynamics in MS is the fatigue/brain fog, which tend to appear in the majority of people with MS regardless of where their specific lesions are. So seems more likely that those specific symptoms have more to do with just the presence of an ongoing immune process somewhere in the brain.
 
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