Study shows how brake cell failure causes some types of seizure disorders

A new study at the University of Bonn has shown that brake cell failure causes some types of seizure disorders. The study, to be published soon in the Journal of Neuroscience, looked at rats with a form of epilepsy called temporal lobe epilepsy (TLE), the most common form found in humans. This is also the most difficult to treat with standard anti-seizure medications. The researchers aimed to find out why this condition arises. They found that it is probably due to the failure of certain specialized brain cells which normally contain the spread of electrical impulses across the brain, or inhibitory interneurons. These have been dubbed “brake cells”.

brain-scan-epilepsyBillion Photos | Shutterstock

Normal brake cell function

Epilepsy is a condition in which seizures repeatedly occur, causing signs and symptoms caused by the excessive or abnormally synchronized activity of clusters of neurons organized in a nerve pathway.  

Certain forms of epilepsy, or seizure disorder, are thought to have been caused by dysfunctional brake cells. The breakdown of these cells leads to the widespread propagation or spread of the brain electrical wave across a major part of the cortex, or gray matter, causing local or generalized muscular contractions to occur. However, proof to underpin this concept has been lacking so far.

The current study focuses on the impaired function of the nerve cells that connect other neurons (“interneurons”) but damp the message being passed through them (“inhibitory”). These, therefore, prevent the spread of an excitatory, or stimulatory, nerve impulse in that area. The inhibitory interneurons studied in this case are of two types: basket cells and OLM interneurons. These are situated within the hippocampus, an area in the temporal lobe of the brain which is most commonly the source of seizures in epilepsy.

Excitatory nerve impulses in the hippocampus pass through specialized cells called CA1 pyramidal neurons, which give rise to pulses of higher voltage when stimulated by an electrical current. The voltage pulse, in turn, passes through a feedback loop to stimulate the inhibitory interneurons as well. These respond by damping the pyramidal cells themselves – which is called inhibitory feedback regulation. Thus, the excitatory impulse is prevented from spreading outward without limit. If the stimulus was sufficient to cause a seizure, it would stop right there before spreading to other parts of the brain. These interneurons, therefore, gate excitatory signals to other parts of the brain.

The mechanism of failure

The study found that in rats with TLE, these brake cells appear to be at fault. The scientists built a computer simulation of how pyramidal cells and brake cells interact. They modified the virtual brake cell’s characteristics to exactly replicate the actual cell’s behavior in the TLE rats.

The sick cells in the rats with TLE appeared to show two types of dysfunction. Firstly, the interneurons secreted only a fraction of their stored inhibitory neurotransmitter in response to the pyramidal cell stimulation. Secondly, their membranes were not able to keep up the electrical gradient normally, instead acting as if a slight leakage was present. This combination of factors led to a profound loss of brake cell readiness to be activated normally by the stimulatory impulse from the pyramidal cells. This caused a significant decrease in the amount of inhibition that occurs, allowing the excitatory impulse from the pyramidal cells to pass outwards without weakening.

Also, inhibitory interneurons are recruited by excitation from a feedback loop. The large change in the time at which this inhibition is brought to act upon the forward positive feedback loop causes a dramatic lack of inhibition at the beginning of the pyramidal cell activity caused by an excitation stimulus.  

Researcher Heinz Beck says this is only the start of a new line of research. “First we have to find out whether the two disruptions are actually responsible for the malfunction of the interneurons. If so, this may open the way to new therapeutic approaches in the long term.” Even so, decades of research lie ahead before these findings can be of any possible clinical benefit to patients.

Journal reference:

Altered dynamics of canonical feed-back inhibition predicts increased burst transmission in chronic epilepsy. Leonie Pothmann, Christian Klos, Oliver Braganza, Sarah Schmidt, Oihane Horno, Raoul-Martin Memmesheimer, & Heinz Beck. The Journal of Neuroscience, 2019; 2594-18 DOI: 10.1523/JNEUROSCI.2594-18.2019. https://www.jneurosci.org/content/early/2019/09/11/JNEUROSCI.2594-18.2019

Dr. Liji Thomas

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Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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