Glial cells keep appearing everywhere I look. No, I have not been shrunken by some Rick Moranis-like character and made to wander around the body (a reference to “Honey, I shrunk the kids”)! But, I have been wandering around the pages of journals, ever-so-slowly trying to get a grasp of how the nervous and immune systems talk to each-other. What usually stands out? Any description of the local and distant effects (and their mechanisms) of illness and injury. So here is my shortest possible take on one interesting study from a group in Switzerland.
Step 1:
Glial cell (e.g. astrocyte): thought to affect the firing at synapses (neuromodulation).
Glutamate: Astrocytes produce glutamate and keep it contained in internal pockets. When required, these pockets slowly move like little amoebas towards the astrocytic membrane. There they join up, open up, and spit out their contents.
Neuromodulation: An astrocyte, adjacent to a nerve synapse, fires. The astrocyte spits out glutamate. This makes the neighbouring nerve fire across its synapse.
Cytokine TNF-α: we always carry it in small amounts but add an injury or disease and the amount increases.
Step 2:
According to this study, remove TNF-α and the astrocyte glutamate system breaks down. Basically, the pockets of glutamate still join with the membrane but the process slows down like a truck in peak-hour traffic.
Why does this stop the astrocytic-stimulation of firing at the adjacent synapse? Astrocytes are always capable of slowly removing glutamate that they have released. But normally so much glutamate is released that the astrocytic clean-up system is overwhelmed and the adjacent synapse is stimulated. However, since the absence of TNF-α slows the glutamatergic-release system, the astrocytes can now slurp up the little glutamate that has been spat out and the potentiation of nerve firing does not take place.
Furthermore, the effect of TNF-α on the glutamate-release system is dependent on the concentration of TNF-α. At constitutive concentrations, TNF-α allows the glutamate mechanism to work. But increase the concentration of TNF and the glutamate release is directly stimulated. In other words, at higher concentrations TNF-α directly causes the synapse to fire.
Why is this interesting? Firstly, this is one small example of how injury and infection can modulate synaptic efficiency and activity. Secondly, this is another reminder of the complexity behind the fine homeostatic balancing act in which our bodies engage constantly. Lastly, this work was done on cells from the dentate gyrus in the hippocampus. This region is thought to be related to memory, depression, and stress. And, after all, my personal interest is in discovering mechanisms that may eventually uncover a tiny piece of the puzzle to our understanding of how illness can lead to systemic effects and neuroplasticity.
Luke Parkitny
Luke Parkitny is a PhD student at Neuroscience Research Australia. He is researching some of the factors that play a role in the development of complex regional pain syndrome (CRPS). Luke joins the Body in Mind team with a background of clinical practice and research in Western Australia. He has rapidly cultivated an interest in all things pain and has very successfully exploited every opportunity to share this knowledge with other health professionals and lay-persons. Link to Luke’s published research and here he is in person talking about what he does.
Reference:
Santello M, Bezzi P, & Volterra A (2011). TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron, 69 (5), 988-1001 PMID: 21382557
Hi Luke – nice post – Luke highlights some very important points here, the most important is that cytokine-glia-neurotransmitter- neuron interactions have their own homeostatic mechanism. The key thing however is that modern, and in my opinion, misguided pharma are leading strategies that attempt to indiscriminatively block compounds such as TNF-alpha that have been identified as having algogenic roles. These approaches ignore the pleiotropic roles of cytokines such as TNF. They may appear to be sensible strategies at first but may have detrimental effects within these homeostatic systems. We are in the embryology of understanding of neuro-immune
interactions especially in the brain – more research will add to our understanding and most likely to the complexity of these systems.
[Reply]
Neil O'Connell Reply:
January 25th, 2012 at 1:18 am
Interesting point Mick, but are you being a bit hard on pharma. The standard model is find a pathway, look for a compound to block it, then test it. Of course if you have an effect there will doubtless be side-effects but from a pharma perspective it seems less likely that one could find a compound with a specific effect that matches the elegance of the system it hopes to effect. We just have to test and hope the benefits outweight the risks?
[Reply]
Mick. Firstly, thank you for the encouragement.
I agree that we face the increasing (and difficult) realisation that many or even most pathological responses have a grounding in normal physiological function. It’s the classic “too-much-of-a-good-thing” argument.
In terms of therapies, this creates a situation where we are forced to design treatments that limit the extreme reaction without completely discontinuing the useful function of that particular bodily function (a wonderfully classic example lies in the measures we have to take to suppress the immune system following an organ transplant). But this is just breaking the surface! Because then we realise that all these systems interact with each-other, and the complexity inherent in fine-tuning therapies starts to sky rocket.
For the scientist-part of us, this is all very fascinating and exciting (seeing that so much fine-tuning goes on behind the “big picture” and that all that is just sitting there waiting to be understood).
For the clinician-part of us, this means that we will probably always have to be content with treatments that maximise the desired effect and minimise the side-effects (i.e. choose acceptable cost:benefit).
[Reply]