Epilepsy is an extremely varied condition, with many possible causes, not all of which have been established.

Some forms of epilepsy have a known genetic cause, and in these cases if the DNA of an affected person is analysed, the abnormal
gene(s) can be seen. Occasionally, however, people have no apparent genetic susceptibility to epilepsy, but experience an initial seizure and go on to develop the condition. There is usually a time lag between the first seizure and the development of epilepsy, known as the latent period.

Until recently, the reason why this happens was not clear; however researchers from the Wake Forest School of Medicine in North Carolina, USA, have now found some answers. They have discovered a gene that when inherited in its mutated active form can cause epilepsy, but whose 'normal' inactive form can also be switched on by an initial seizure.

The gene in question encodes a specific calcium channel in the brain. There are many different types of calcium channel in the body, and these are responsible for several key functions, depending on their location and number. The calcium channels in the brain are normally embedded within the membrane of cells and neurons, and here they allow calcium ions to enter. Calcium ions, along with sodium and potassium ions are responsible for the electrical activity of neurons. It has been shown that if calcium channels are not functioning properly, or if they appear in the wrong place, this can disturb the electrical activity in the region and make the neurons there hyperactive. In addition the movement of calcium ions determines how easily abnormal activity spreads throughout the brain.

Epilepsy studies usually involve the hippocampus of the brain (an important memory centre); however the team in North Carolina decided to extend their analysis to the thalamus, because it is connected to the hippocampus and is known to help the spread of seizures.

They took 60 animal models and injected them with a chemical known as pilocarpine, to induce status epilepticus (SE). SE is defined as a seizure that lasts 30 minutes or longer, or a series of seizures without consciousness being regained in between. A separate group was injected with a saline solution, and this served as a control. The researchers examined all of the models at 4 hours, 10 days and 31 days after injection, for presence of three calcium channels known as CaV3.1, CaV3.2, and CaV3.3. The number and location of each channel was a direct indication of the activity of the genes that encode or 'express' them. The timings were selected to represent acute SE (4 hours), the latent period (10 days) and epilepsy / chronic spontaneous recurrent seizures (SRS) (31 days).They also looked at the hippocampus of each brain at 10 days and 31 days for the same channels.

In the experimental group, SE was successfully induced in 55 models. At 4 hours, there was no difference in gene expression of calcium channels between experimental and control models. By 10 days, CaV3.2 expression had increased 1.8-fold and CaV3.3 expression had risen 1.7-fold in the thalamus; but there were no changes seen in any of the channels in the hippocampal samples.

At 31 days, only CaV3.2 expression was altered, increasing 2.1 times in the thalamus compared to controls. However interestingly, expression of this channel had decreased 2-fold in the hippocampus (relative to controls).

John Graef, a student and the first author on the study, commented on their findings:
"Certain kinds of channels are normal and expected in the thalamus, but after an initial seizure more copies of a channel that isn't normally found in this brain region begin to appear. The brain activity then becomes dominated by the new copies of this channel. It helps explain how seizures can develop and spread."

The scientists then examined groups of neurons in the thalamus and hippocampus, to see if the changes in calcium channel number seen actually affected their electrical activity. They found that the new arrangement of channels reduced the number of 'burst' responses seen during the latent period and promoted increased hyperexcitability during the chronic SRS phase.

These results are significant, because they suggest that there is a gene for the CaV3.2 channel that is normally inactive, but can be switched on by an initial seizure.

Dr Dwayne Godwin, a collaborator on the project, summarised their findings: "What we've shown is that this gene can be switched on in individuals who don't appear to have inherited the susceptibility."

As the culprit gene can't always be identified (i.e. it can be inherited in its normal form), it is difficult to use DNA analysis to predict who is susceptible. However, if we could somehow prevent the increase inCaV3.2 channels after a one-off seizure, it might be possible to stop the subsequent development of epilepsy.

A compound called ascorbate has recently been shown to inhibit CaV3.2 channels specifically. The next step will be to investigate the effects of ascorbate on CaV3.2 channels during chronic SRS, and see if it could play a role in the prevention / treatment of some forms of epilepsy in the future.

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