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Migration of Dentate Granule Cells in Epilepsy

Microscopic imaging technique depicts movement of individual neurons

Migration of Dentate Granule Cells in Epilepsy

Motility of granule cells under epileptic conditions. Life cell imaging of individual eGFP-labeled granule cells performed over a period of 8 hours. Some cells, which were tracked, are marked by green frames. (A) Cells remain in place. (B) Granule cells s

Researchers from the Medical Center – University of Freiburg, the Bernstein Center Freiburg, and the cluster of excellence BrainLinks-BrainTools have provided new insights into the migration of dentate granule cells in epilepsy – neurons that should not migrate in a healthy adult brain. With the help of life cell imaging, an approach that involves time-lapse microscopy and fluorescent proteins to observe cells in a living condition, the researchers were able to trace this migration over a period of eight hours. This approach enabled Catarina Reis Orcinha and Gert Münzner from the Group of Prof. Carola Haas to provide a dynamic visualization of the migration of dentate granule cells. Their findings were now published in the scientific journal Frontiers of Cellular Neuroscience.

But what causes the migration of these nerve cells? “It is the absence of a protein called Reelin. In the healthy brain dentate granule cells use Reelin as a positional cue. This is important during development, when neurons have to migrate over large distances,” Orcinha answers. Reelin is secreted by so-called Cajal-Retzius cells which are located in the marginal layer of the developing cerebral cortex or in the hippocampus. These neurons die as a result of temporal lobe epilepsy, causing the dentate granule cells to migrate towards the location where the loss of Reelin occurred. “Here they are likely to form new connections where they should not be, causing chaos”, Orcinha adds, “one of the potential reasons for epileptic seizures.”

With the help of organotypic slice cultures, a slicing technique that preserves brain in its structure, Orcinha and Münzner were able to conduct their experiments in the living cellular environment of an ‘artificial’ hippocampus. “In our study, we focused on a specific fragment of Reelin. This central fragment of the protein is called R3-6. Many publications have shown before that this fragment is crucial for the receptor binding of this protein,” explains Orcinha. The researchers began by applying kainate, a natural marine acid, to the slice to make it epileptic and promote cell migration. Applying the protein fragment in a very low and controlled concentration during the imaging session conveyed that its application slowed down the cell migration.

The researchers want to understand how it is possible that neurons, which are normally fixed in place, migrate under pathological conditions. “In the healthy brain, the connections are dynamic only on a very small level. There is a certain dynamic, but not in terms of long range migration or anything as such,” group leader Carola Haas explains. Thus, regaining control over migrating cells and even returning the network into its initial state could be devised as an approach for a potential treatment of epilepsy.

So, is an injection or a Reelin pill a therapeutic option? “The answer is no,” Haas remarks. “Reelin is a very large molecule and therefore it would never cross the blood-brain barrier. However, one could envisage the design of small molecules that could cross the blood-brain barrier and target the Reelin receptors.” Such molecules could have a completely different structure as Reelin itself. “But I’m afraid this is a distant vision,” Haas concludes.

 

Results and visualizations:
http://journal.frontiersin.org/article/10.3389/fncel.2016.00183/full

Original publication:
Orcinha C, Münzner G, Gerlach J, Kilias A, Follo M, Egert U and Haas CA (2016) Seizure-Induced Motility of Differentiated Dentate Granule Cells Is Prevented by the Central Reelin Fragment. Front. Cell. Neurosci. 10:183. doi: 10.3389/fncel.2016.00183.

Caption:
Motility of granule cells under epileptic conditions. Life cell imaging of individual eGFP-labeled granule cells performed over a period of 8 hours. Some cells, which were tracked, are marked by green frames. (A) Cells remain in place. (B) Granule cells show increased motility (white arrows).GCL, granule cell layer; H, hilus.


Contact:
Prof. Dr. Carola Haas
Neurozentrum der Albert-Ludwigs-Universität
Experimentelle Epilepsie
Breisacher Strasse 64
79106 Freiburg i.Br.
Tel.: +49 (0)761 270 5295 0
E-Mail: carola.haas@uniklinik-freiburg.de


 

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