IEC 2025 | Potential mechanisms underlying resilience to epileptogenesis in the adult brain

One of the potential mechanisms of resilience for the brain to develop epilepsy, and this is in the adult brain, was presented by Dr Javier Ramos from UVA in Argentina. And what he showed was that the astrocytes after an epileptogenic brain insult, so, for example, pilocarpine, traumatic brain injury, or any other models of chemically or electrically induced epilepsy, the astrocytes change from a homeostatic astrocyte into a pathologically remodeled astrocyte. And the problem with this astrocyte is that it becomes epileptogenic, so it sort of promotes the development of epilepsy. And this astrocyte has many changes, so it has changes at the molecular level on the toll-like receptor 2 and 4 pathways, and these pathways, and also the pathway of something called NF kappa beta, they are critical for two reasons: one of them is because they increase inflammatory cytokines like IL-1 beta, IL-6, that on its own, they increase inflammation, so they increase the risk to develop epilepsy, but also it modifies different epigenetic signatures of the astrocytes, which also makes that change from a pathological astrocyte. And what happens is that this astrocyte is not supporting the neurons anymore, so it’s not helping with the glutamate uptake or buffering of potassium. And also, that causes neuronal degeneration, which, as many people can appreciate. So, you have more neuroinflammation, you have more neuronal degeneration. So, it creates like this vicious cycle that the astrocytes are not working the way they’re supposed to work, and they’re promoting the development of epilepsy. And so, what Dr Ramos showed is that by modification with certain drugs that could alter that change, pathological change in astrocytes, you could potentially prevent the development of epilepsy. And that was sort of a novel mechanism, especially thinking outside of the box, that, you know, seizures, obviously, the neurons are important, but also the glial cells, particularly astrocytes, have been overlooked, but there’s lots of people that are investigating more about them lately. I think another potential mechanism, and that was discussed, that was a really interesting work by Dr Jennifer Wong from Emory University in the United States. So, Dr Wong showed that potential genetic modifiers for epilepsy and Alzheimer’s disease. So, some of the work that Dr Wong presented was that reducing the SCN8A expression of this gene in the mouse model resulted in increased tissue resistance, which was quite interesting to see. But what was also sort of groundbreaking was that if you manipulate the expression of this gene SCN8A in a mouse model of Alzheimer’s disease, then if you reduce the expression of this gene, the animals of this Alzheimer’s disease model, they will have normal behavior and normal lifespan. So, it seems that by decreasing the expression SCN8A in a model of Alzheimer’s disease is actually beneficial, which was quite interesting. And then Dr Wong, what she did was do the opposite. So, okay, so we reduce, what happens if we increase. So, if you increase the activity of SCN8A in a mouse model of epilepsy, then it increases the susceptibility for the animal to develop epilepsy. And if you increase now the expression of this SCN8A gene in a mouse model of Alzheimer’s disease, it makes everything worse from the model. So, you see increased premature mortality, increased anxiety-like behavior, worse spatial memory deficits, and more Alzheimer’s neuropathology. So, one of the ideas that Dr Wong presented is that modulating the SCN8A expression could increase the resilience in epilepsy, but also in potentially other neurological disorders that share that neuronal hyperexcitability, such as Alzheimer’s disease.

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