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Zebrafish On A Swing

zebrafish

A failure of glial cells in the brain underlies the triggering of an epileptic seizure, a recent study from Norway suggests.

The research group studied epileptic seizures in zebrafish (Danio rerio). One advantage of these fish over the usual rodent model is they are transparent, so activity in their nervous system is easier to observe.

You might be wondering how researchers get zebrafish to have seizures. Well, it would have been more interesting if they had used strobe lights in a darkened room, but in this case they used drugs (a convulsant called Pentylenetetrazol was added to a tank full of zebrafish larvae, a standard epilepsy laboratory model).

I did want to throw in this great explanation of how flashing lights can trigger an epileptic episode. In a recent Reddit thread[1], user BennyPendentes wrote:

“If you push a kid on a swing, gravity and air-resistance slow them down and they swing less further each time, eventually stopping at the bottom. If you push them at random times, you might speed them up one time then slow them down the next. But if you time it right, adding new energy in at just the right time, you can make them swing higher and higher. A seizure, in this analogy, would be like repeatedly adding so much energy that the kid goes around and around in a full circle, the chain wraps around the top pole, and everything comes to a tragic halt when the length of free chain becomes less than the thickness of the kid.”

Well, more or less. It depends on the type of seizure a person has.[2]

The Norwegian research group was able to identify typical patterns just before and during the epileptic seizures.

Seizure Patterns

In the beginning phase, just before an epileptic seizure, nerve cells were abnormally active but only in spatially localized area of the brain. Instead, glial cells showed large bursts of synchronous activity, widely dispersed across the brain.

In zebrafish, this activity in the glial cells looked like lightning shooting through the brain.

zebrafish brain top
A confocal micrograph of the anterior region of the developing zebrafish brain
Credit: Dr Steve Wilson. CC BY

During the actual seizure, the neuronal activity increased abruptly. The functional connections between the nerve cells and glial cells, and between different glial cells, became very vigorous. When this happened, generalized seizure spread like a storm of electrical activity across the entire brain.

During the generalized seizure, the research group also noted a strong increase in the level of the neurotransmitter glutamate.

What is happening in this shift from a balanced resting state to a hyperactive and unsynchronised state?

Although many studies have provided useful information on how different brain areas are connected, they fail to clarify how these complex systems are organized and tell us little about the underlying mechanism that drives epileptic changes in connectivity.[3]

Increasingly, scientists are making use of network theory to investigate epileptic seizures. So let’s take a quick detour through that.

Network theory is the study of graphs as a representation of relations between discrete objects. In computer science and network science, network theory is a part of graph theory: a network can be defined as a graph in which nodes and/or edges have attributes.

In neuroscience, network theory serves as a novel approach to the analysis of brain structure and function. It represents a different view of brain activity and brain-behavior mapping, shifting from a computer mechanism-like model to a complex system vision of the brain.

The clustering coefficient and path length
The clustering coefficient and path length. Brain network schematic of nodes (circles) and edges (black lines). The clustering coefficient is based on triangles (one triangle shown in blue) and is equivalent to the fraction of the node’s neighbors that are also neighbors of each other. The path length in a binary network is the minimal number of edges that must be traversed to travel from one node to another. In red an example path is shown which contains the least number of edges (i.e. three) between the two uniform red nodes.
Credit: van Diessen, et al. CC-BY

In this model, networks are suffused with properties which arise fundamentally from characteristics of their component nodes. Structural connections or functional interactions between brain areas are the edges here, with brain areas being the nodes.

Two measurements have been widely used to characterize brain network organization – the path length and clustering coefficient.

Now, what happens to these networks during an epileptic seizure?

A meta-analysis of focal seizures[4] found that interictal (the period between seizures) whole brain networks are characterized by a less integrated and more segregated organization in focal epilepsies.

From a neurobiological viewpoint, the predominant theory is that the continuous accumulation of local neural activity is what unleashes the subsequent cascade of events. In human patients, this may be initiated due to a disease state, injury or malformation in the brain.

The strong firing by the glial cells before the seizure probably represents the protective function of glial, as glial activity bursts before the seizures corresponds to transient silencing of neurons during pre-seizure state.

“The hyperactivity of the glial cells before a seizure is most likely a defense mechanism. The glial cells are known to absorb the excess glutamate secreted during the increased activity of the nerve cells,”

said Nathalie Jurisch-Yaksi, group leader at Norwegian University of Science and Technology’s Department of Clinical and Molecular Medicine and a partner in the zebrafish study project.

The glial cells thus temporarily prevent the nerve cells’ overproduction of excitatory neurotransmitters from leading to a seizure.

But the glial cells only sustain this protective function for a transient period, until it becomes too much neural activity to handle.

“We believe that at some point the defences break down. The glial cells become unable to absorb the high levels of the glutamate neurotransmitter. When it gets to be too much for them, the glial cells simultaneously release all the glutamate they’ve already absorbed. Suddenly the brain is hit with a very high level of glutamate. We believe this excessive release of glutamate by the glial cells leads to a generalized seizure spreading across the brain,”

said Carmen Diaz Verdugo, a Ph.D. candidate.

Hence, a massive increase in glutamate overwhelms the brain, leading to a seizure.

The findings could also indicate that epilepsy may occur not only due to anomalies in neurons, but also can be related to the pathological conditions in glial cells, and abnormal interactions between glia cells and neurons.

Previous studies of patients and in animal models have shown that the properties of the glial cells change after repeated epileptic seizures. But less was known about how the function of the glial cells changes before and during the seizures.

In recent decades, a number of new epilepsy drugs have been developed, but a third of patients still do not have good control over seizures. One reason may be that the current anti-epileptic drugs mostly target the neurons, while the glial cells, which constitute ~80% of the cells in the brain, have been overlooked.

Given all this, gaining new knowledge about the role of glial cells in epilepsy, on the long term, could inspire novel therapies for patients suffering from seizures.

It is already known that some diseases associated with damage to the glial cells may increase the risk of epileptic seizures. Examples of such diseases are gliomas (brain tumors arising from glial cells) and multiple sclerosis. Moreover, damage to the glial cells is also observed in patients with Parkinson’s disease and Alzheimer’s disease, for instance.

Footnotes:

[1] Why do flashing lights trigger a seizure?

[2] Generalized seizures affect both sides of the brain, and fall into two categories

Absence seizures, sometimes called petit mal seizures, can cause rapid blinking or a few seconds of staring into space.

Tonic-clonic seizures, also called grand mal seizures can cause muscle jerks or spasms and loss of consciousness

There are also Focal seizures that are located in just one area of the brain. These are also called partial seizures.

Simple focal seizures affect a small part of the brain. These seizures can cause twitching or a change in sensation, such as a strange taste or smell.

Complex focal seizures can make a person with epilepsy confused or dazed. The person will be unable to respond to questions or direction for up to a few minutes.

Secondary generalized seizures begin in one part of the brain, but then spread to both sides of the brain. In other words, the person first has a focal seizure, followed by a generalized seizure.

[3] Eric van Diessen, et al. Functional and structural brain networks in epilepsy: What have we learned?  Epilepsia, 54(11):1855–1865, 2013

[4] van Diessen E, Zweiphenning WJEM, Jansen FE, Stam CJ, Braun KPJ, Otte WM (2014) Brain Network Organization in Focal Epilepsy: A Systematic Review and Meta-Analysis. PLoS ONE 9(12): e114606