Epileptic Seizures May Be Linked to an Ancient Gene Family

Epileptic Seizures May Be Linked to an Ancient Gene Family

  9:20:00 PM    Science Lover

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New research points to a genetic route to understanding and treating epilepsy. Timothy Jegla, an assistant professor of biology at Penn State University, has identified an ancient gene family that plays a role in regulating the excitability of nerves within the brain.

Artist's depiction of neurons firing in the brain. 
(Credit: iStockphoto/Sebastian Kaulitzki)

The research appears in the journal Nature Neuroscience.

"In healthy people, nerves do not fire excessively in response to small stimuli. This function allows us to focus on what really matters. Nerve cells maintain a threshold between rest and excitement, and a stimulus has to cross this threshold to cause the nerve cells to fire," Jegla explained. "However, when this threshold is set too low, neurons can become hyperactive and fire in synchrony. As excessive firing spreads across the brain, the result is an epileptic seizure."

Managing this delicate rest-excitement balance are ion channels -- neuronal "gates" that control the flow of electrical signals between cells. While sodium and calcium channels help to excite neurons, potassium channels help to suppress signaling between cells, increasing the threshold at which nerves fire. However, the genetic mechanisms that control the potassium channels and set this threshold are not fully understood. Jegla's team focused on a particular potassium-channel gene -- called Kv12.2 -- that is active in resting nerve cells and is expressed in brain regions prone to seizure.

"We decided that Kv12.2 was a good candidate for study because it is part of an old gene family that has been conserved throughout animal evolution," Jegla said. "This ancient gene family probably first appeared in the genomes of sea-dwelling creatures prior to the Cambrian era about 542-million years ago. It is still with us and doing something very important in present-day animals." Previous studies have suggested that the Kv12.2 potassium channel has a role in spatial memory, but Jegla and his team focused on how it might be related to seizure disorders.

In collaboration with Jeffrey Noebels at Baylor College of Medicine, the team used an electroencephalography (EEG) device to monitor the brains of mice. They found that mice missing the Kv12.2 gene did indeed have frequent seizures, albeit without convulsions. The team then stimulated mice with a chemical that induces convulsive seizures. They found that normal mice had a much higher convulsive-seizure threshold than mice with a defective Kv12.2 gene. The team also found the same results when they used a chemical inhibitor to block the Kv12.2 potassium channel in normal mice.

"In mice without a functioning Kv12.2 gene, nerve cells had abnormally low firing thresholds. Even small stimuli caused seizures," Jegla explained. "We think that this potassium channel plays a role in the brain's ability to remain 'quiet' and to respond selectively to strong stimuli."

Jegla hopes to open up new avenues of epilepsy research by studying whether activation of the Kv12.2 potassium channel in normal animals can block seizures. "Ion-channel defects have been identified in inherited seizure disorders, but many types of epilepsy don't have a genetic cause to begin with," Jegla explained. "They are often caused by environmental factors, such as a brain injury or a high fever. However, the most effective drugs used to treat epilepsy target ion channels. If we can learn more about how ion channels influence seizure thresholds, we should be able to develop better drugs with fewer side effects."

In addition to Jegla and Noebels, other scientists who contributed to this research include Xiaofei Zhang, Federica Bertaso, Karsten Baumgärtel, and Sinead M. Clancy of the Scripps Research Institute; Jong W. Yoo of the Baylor College of Medicine; and Van Lee, Cynthia Cienfuegos, Carly Wilmot, Jacqueline Avis, Truc Hunyh, Catherine Daguia, and Christian Schmedt of the Genomics Institute of the Novartis Research Foundation. This research was funded by the National Institutes of Health through its National Institute for Neurological Disorders and Stroke.

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New Nerve Cells -- Even in Old Age: Researchers Find Different Types of Stem Cells in the Brains of Mature and Old Mice

New Nerve Cells -- Even in Old Age: Researchers Find Different Types of Stem Cells in the Brains of Mature and Old Mice

  10:25:00 AM    Science Lover

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After birth the brain loses many nerve cells and this continues throughout life -- most neurons are formed before birth, after which many excess neurons degenerate. However, there are some cells that are still capable of division in old age -- in the brains of mice, at least. According to scientists from the Max Planck Institute of Immunobiology in Freiburg, different types of neuronal stem cells exist that can create new neurons. While they divide continuously and create new neurons in young animals, a large proportion of the cells in older animals persist in a state of dormancy. However, the production of new cells can be reactivated, for example, through physical activity or epileptic seizures. What happens in mice could also be applicable to humans as neurons that are capable of dividing also occur in the human brain into adulthood.

Different types of stem cells in the brain of mature mice. 
(Credit: Verdon Taylor (from: Lugert et al., 
Cell Stem Cell, May 7th, 2010))

The research is published in the journal Cell Stem Cell.

You can't teach an old dog new tricks. The corresponding view that the brain loses learning and memory capacity with advancing age prevailed for a long time. However, neuronal stem cells exist in the hippocampus -- a region of the brain that plays a central role in learning and memory functions -- that can produce new nerve cells throughout life. It is known from tests on mice that the newly formed cells are integrated into the existing networks and play an important role in the learning capacity of animals. Nonetheless, the formation of new cells declines with age and the reasons for this were unknown up to now.

Together with colleagues from Dresden and Munich, the Freiburg researchers have now succeeded in explaining for the first time why fewer new neurons are formed in the adult mouse brain. They managed to identify different populations of neuronal stem cells, thereby demonstrating that the hippocampus has active and dormant or inactive neuronal stem cells. "In young mice, the stem cells divide four times more frequently than in older animals. However, the number of cells in older animals is only slightly lower. Therefore, neuronal stem cells do not disappear with age but are kept in reserve," explains Verdon Taylor from the Max Planck Institute of Immunobiology.

The precise factors that influence the reactivation of dormant stem cells are not yet clear. The cells can, however, be stimulated to divide again. The scientists observed more newborn hippocampal neurons in physically active mice than in their inactive counterparts. "Consequently, running promotes the formation of new neurons," says Verdon Taylor. Pathological brain activity, for example that which occurs during epileptic seizures, also triggers the division of the neuronal stem cells.

Horizontal and radial stem cells

The different stem cell populations are easy to distinguish under the microscope. The first group comprises cells which lie perpendicular to the surface of the hippocampus. Most of these radial stem cells are dormant. As opposed to this, over 80% of the cells in the group of horizontal stem cells -- cells whose orientation runs parallel to the hippocampus surface -- continuously form new cells; the remaining 20% are dormant but sporadically become activated. The activity of genes such as Notch, RBP-J and Sox2 is common to all of the cells.

Radial and horizontal stem cells differ not only in their arrangement, apparently they also react to different stimuli. When the animals are physically active, some radial stem cells abandon their dormant state and begin to divide, while this has little influence on the horizontal stem cells. The result is that more radial stem cells divide in active mice. The horizontal stem cells, in contrast, are also influenced by epileptic seizures.

It would appear that neuronal stem cells are not only found in the brains of mice. The presence of neurons that are formed over the course of life has also been demonstrated in the human hippocamus. Therefore, scientists suspect that different types of active and inactive stem cells also arise in the human brain. It is possible that inactive stem cells in humans can also be activated in a similar way to inactive stem cells in mice. "There are indicators that the excessive formation of new neurons plays a role in epilepsy. The use of neuronal brain stem cells in the treatment of brain injuries or degenerative diseases like Alzheimers may also be possible one day," hopes Verdon Taylor.

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