http://bodyinmind.org/immune-system-in-neuroplasticity/
Neuroimmunology for idiots. Part 3: Immune system in neuroplasticity
In this, the oddly named 4th part of this little series, I am trying to get my head around the role of cytokines in facilitating long term potentiation and nurturing neuroplasticity. The key work in this field seems to be this[1] These guys were the first to show that an inflammatory-like process, the secretion of pro-inflammatory cytokine IL-1, occurs in key brain areas in association with long term potentiation – a process that Hebb described as ‘neurons that fire together, wire together’[2]. Other researchers have gone on to do the the usual things – show a relationship between LTP and IL-1 levels, show no LTP when IL-1 antagonist is injected, show no LTP in mutant mice without IL-1 manufacturing gene[3]. Here is where the story gets a bit juicier because the role of IL-1 is not just limited to the hippocampus and to spatial and related memory formations. IL-1 expression is associated with LTP in the dorsal horn, specifically at spinal nociceptors – the spinal projection of C-fibres – I am sure Mick Thacker or Mark Hutchinson could tell us about that, if either of you are watching….
IL-6, our swinging voter, sometimes anti-inflammatory sometimes pro-inflammatory, might have an important role in turning LTP off. That is, IL-6 is upregulated 4-8 hours after high-frequency stimulation of a mouse’s hippocampus, but if IL-6 is blocked by IV anti-IL6 antibodies, then LTP persists for longer4. So, stimulating the hippocampus, an experimental model of intensive spatial learning, increases IL-1 and IL-6 expression. IL-1 seems to be particularly important in establishing LTP and IL-6 seems to be important for turning it off. Extrapolating now to things we do not want to potentiate, one wonders if augmenting IL-6 might reduce the likelihood of LTP in the nociceptive system after acute injury, or in the circuits that subserve post traumatic stress syndrome. It would seem a pretty tough ask to do anything to IL-1 expression simply because of the time window, but IL-6? Could we get in there within 6 hours of the trigger? I reckon it is a chance. Anyone know of research to this effect? Mick? Mark?
If IL-1 and IL-6 are involved in LTP in the acute setting, TNF-α saves itself for later – mice that have impaired TNF signaling show normal acute LTP. However, animal vision experiments show that when TNF-α signaling is blocked genetically or by drugs, the animal does not show the normal adaptation of visual brain circuits, adaptations that are dependent on very LTP – plasticity that takes a long time to occur and involves structural changes for example pruning of dendrites and establishment of new synapses5. This too has clear potential implications for chronic pain and PTSD – we know that functional and structural changes occur in the brain in people with chronic pain and PTSD – it is possible that TNF-α is somehow involved in this? In CRPS research, TNF-α expression is heightened and there is some evidence that anti-TNF-α treatment can be effective, although more work is required – here is a great review by Frank Birklein and here is Frank Birklein!
Finally, the prostaglandins. No surprises here – prostaglandins have a role in LTP – the usual methods have shown this. Again though, this might have a direct application to us – selective COX-2 inhibitors impair LTP in the mouse hippocampus, which raises the possibility, not completely outrageous or remote, that taking a bit of ibuprofen impairs the LTP that contributes to chronic pain. I know that COX-2 inhibitors are proposed to limit the development of chronic pain in several ways, but this is a mechanism I do not immediately think of. We tend to think of anti-inflammatories as a solely peripheral thing, which clearly they are not.
The other thing that is clear is that I need to rescue myself from this slippery slope of neuroimmunology – I can feel it seducing me with its complexity and apparent potential. I aim going to stand my ground, be faithful to my neurocentric roots and delay the last post of this series so I can get back to some of my normal work….
IL-6, our swinging voter, sometimes anti-inflammatory sometimes pro-inflammatory, might have an important role in turning LTP off. That is, IL-6 is upregulated 4-8 hours after high-frequency stimulation of a mouse’s hippocampus, but if IL-6 is blocked by IV anti-IL6 antibodies, then LTP persists for longer4. So, stimulating the hippocampus, an experimental model of intensive spatial learning, increases IL-1 and IL-6 expression. IL-1 seems to be particularly important in establishing LTP and IL-6 seems to be important for turning it off. Extrapolating now to things we do not want to potentiate, one wonders if augmenting IL-6 might reduce the likelihood of LTP in the nociceptive system after acute injury, or in the circuits that subserve post traumatic stress syndrome. It would seem a pretty tough ask to do anything to IL-1 expression simply because of the time window, but IL-6? Could we get in there within 6 hours of the trigger? I reckon it is a chance. Anyone know of research to this effect? Mick? Mark?
If IL-1 and IL-6 are involved in LTP in the acute setting, TNF-α saves itself for later – mice that have impaired TNF signaling show normal acute LTP. However, animal vision experiments show that when TNF-α signaling is blocked genetically or by drugs, the animal does not show the normal adaptation of visual brain circuits, adaptations that are dependent on very LTP – plasticity that takes a long time to occur and involves structural changes for example pruning of dendrites and establishment of new synapses5. This too has clear potential implications for chronic pain and PTSD – we know that functional and structural changes occur in the brain in people with chronic pain and PTSD – it is possible that TNF-α is somehow involved in this? In CRPS research, TNF-α expression is heightened and there is some evidence that anti-TNF-α treatment can be effective, although more work is required – here is a great review by Frank Birklein and here is Frank Birklein!
Finally, the prostaglandins. No surprises here – prostaglandins have a role in LTP – the usual methods have shown this. Again though, this might have a direct application to us – selective COX-2 inhibitors impair LTP in the mouse hippocampus, which raises the possibility, not completely outrageous or remote, that taking a bit of ibuprofen impairs the LTP that contributes to chronic pain. I know that COX-2 inhibitors are proposed to limit the development of chronic pain in several ways, but this is a mechanism I do not immediately think of. We tend to think of anti-inflammatories as a solely peripheral thing, which clearly they are not.
The other thing that is clear is that I need to rescue myself from this slippery slope of neuroimmunology – I can feel it seducing me with its complexity and apparent potential. I aim going to stand my ground, be faithful to my neurocentric roots and delay the last post of this series so I can get back to some of my normal work….
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