Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis
- Neurology
- doi:10.1038/nrneurol.2015.222
- cortical MS lesions – these are frequent in MS, and we know that cortical atrophy occurs early in MS. Synaptic loss is striking in cortical lesions; at a microscopic level ~ 47% is synaptic loss as opposed to cellular loss (i.e. glial and neuronal loss).
- memory/cognition – 30-40% of PwMS are affected. In the hippocampus (where memory is consolidated) demyelination causes alterations in synapses.
Dendrites and synapses are vulnerable to excitotoxicity (see diagram). One immune cell, in particular, keeps cropping up when there is synaptic damage, the microglia. Microglia are the resident macrophages in the brain, and were previously believed to quite static, but now understood to be anything but. Their main role is to remove damaged cells including dysfunctional synapses; a process called “synaptic stripping”. However, in MS they are very much activated resulting in a massive release of TNF (tumour necrosis factor)-alpha, which causes excessive glutamatergic transmission, ultimately cascading to excitotoxicity (see diagram).
All hope is not lost, and we turn to Laquinomod. Laquinomod has little to recommend itself in RRMS (only managing an abysmal 23% relapse reduction compared to placebo) but has this surprising 36% decrease in disability progression and a 33% reduction in brain volume loss. A paradox if ever there was one. This happy coincidence may be explained by Laquinomod’s ability to limit alterations in GABAergic and glutamatergic synapses, thereby limiting glutamatergic excitotoxicity which leads to synaptic implosion (Article: Laquinomod prevents inflammation-induced synaptic alterations occurring in experimental autoimmune encephalomyelitis).
Laquinomod, for example, would have the same side effect of Riluzole in worsening the fatigue felt by MSers?
It shouldn't contribute to conduction blockade, Riluzole you may be aware has sodium channel blocking properties.
Thanks NDG. It seems that Laquinomod will be a promising neuroprotective …
Rather sophisticated for me as a software engineer. However, years back I worked on parallel processing neural networks. I did not know much about MS back then. For example, we'd examine how cascades could happen across a neural network simulation, was all towards engineering.
One of my personal big questions with MS (and perhaps other conditions) is DOES this sort of cascade also happen? I have tried find research and found pretty much nothing. Understandable as attempting measure it with billions of nodes in a living creature is beyond what technology can do. But, if it DOES happen then it may well be key to understanding the connection between attacks, region(s) attacked and triggers. Cascade is essentially misinterpretation by nodes (Which are logic based gates) of the logical AND, OR, NOT conditionals and as these errors cascade through a complex network they cause more growing from low level to higher level error. The CNS would attempt correct I assume which is exactly what we tried do in network models.
The CNS is infinitely more complex. Question I have is "if" the immune system is connected to the brain which new research suggests does the cascade result in a trigger and also point towards where attacks might occur.
Research has generally been based towards the more biological/chemical aspects of MS as again, from an electrical level measurement would be very problematic. Ultimately however CNS signaling is electrical through a biological format of conductors and logic gates.
tDCS for example towards Neuro Plasticity is being studied and other aspects of tDCS.
It might be VERY interesting to see if focused tDCS could result in a flare-up or results of tDCS in an existing flare-up.
An interesting study for example might be low level direct current therapy tDCS
It's infinitely more complex, it's both chemical, biological (i.e. the residents and interlopers), and electrical. The human brain project idea is to tackle the electrical front – $$ project. There is research in connectomics trying to link the biological to the chemical and then physical deficits. And at some stage the two can be linked. The question is whether to study normal or disease first, or the two combined? In answer to your last question transmagnetic stimulation generates an electrical current and is hypothesised to improve mobility.