Just as each musician in an orchestra contributes to the overall sound of a musical piece, different types of nerve cells in the brain make up the symphony of our consciousness.
They regulate and coordinate the activity of groups of neurons that represent parts of information, which they then may transmit to other brain regions. If this precise system is thrown off balance, diseases can develop.
Professor Jochen Meier of the Max Delbrück Center (MDC) investigates such processes. Together with his colleagues, he has gained new insights into epilepsy, showing why the disease may present different symptoms (Journal of Clinical Investigation, doi:10.1172/JC171472)*.
The research focus is on the glycine receptor, known from previous studies in the field of spinal cord research as an inhibitory neurotransmitter receptor. Several years ago the research group of neurobiologists showed that this receptor is molecularly altered in patients with intractable temporal lobe epilepsy, one of the most common forms of epilepsy.
Expression of the altered receptor is increased in the hippocampus, a region of the brain that triggers seizures in most patients at later stages of the disease.
Professor Meier, who leads a Helmholtz junior research group at the explained that epilepsy is not exclusively inherited, that is, its cause need not be genetic. In fact, recent research data indicate that various environmental factors, including chronic stress, can cause epileptic seizures.
Resulting molecular and cellular mechanisms may change neuroplasticity to the extent that the affected tissue is no longer able to restore the normal state, which can then lead to chronic epilepsy. This may be one reason why the disease course differs from patient to patient.
The molecular alteration of the glycine receptor in the tissue of epilepsy patients is caused by a process known in research as “RNA editing”. Thereby, in the process of transcription of genetic information from DNA to RNA, individual letters are replaced with others. Enzymes are responsible for the editing of the text.
As a result, the original genetic text encoded in the DNA language no longer corresponds exactly to the RNA, which contains the code for the text building blocks of the proteins. The protein, in this case the glycine receptor, is altered so that it expresses a gain-of-function, and thus functions far more effectively than its non-edited counterpart.
Together with colleagues from Israel and different German universities, Dr. Aline Winkelmann and Professor Meier developed a new animal model of epilepsy to determine the role of this particular glycine receptor variant. This allowed them to express this receptor specifically in selected nerve cell types of the hippocampus and to investigate how it affects cognitive function and mood-related behavior.
They found that the RNA-edited gain-of-function receptor targets the presynaptic terminals, which transfer electrical impulses by releasing a neurotransmitter to other nerve cells. Thus, the function of selected types of nerve cells is strengthened, whereby the whole system of neuronal communication is thrown off balance.
Depending on whether excitatory or inhibitory nerve cells expressed the receptor, the mice were impaired in their cognitive abilities including memory deficits, or they showed increased anxiety.
“Our new animal model suggests that the same molecule can contribute to a wide range of symptoms in epilepsy patients – for example, cognitive dysfunction or anxiety – depending on which type of nerve cell expresses it,” Professor Meier said.
He and his colleagues have thus discovered a disease mechanism which they hope will open up new approaches to the development of targeted treatments for epilepsy patients. He stressed, however, “We must also identify the conductor of this cellular orchestra of dissonant molecular components that is responsible for receptor expression in varied nerve cells in the hippocampus of epilepsy patients.”
*Changes in neural network homeostasis trigger neuropsychiatric symptoms
Aline Winkelmann,1,2 Nicola Maggio,3 Joanna Eller,4 Gürsel Caliskan,5 Marcus Semtner,2 Ute Häussler,6 René Jüttner,7 Tamar Dugladze,4 Birthe Smolinsky,8 Sarah Kowalczyk,8 Ewa Chronowska,9 Günter Schwarz,8 Fritz G. Rathjen,7 Gideon Rechavi,10 Carola A. Haas,6,11 Akos Kulik,9,12 Tengis Gloveli,4,13 Uwe Heinemann,5 and Jochen C. Meier2
1FU-Berlin, Fachbereich Biologie, Chemie, Pharmazie, Berlin, Germany. 2RNA editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany. 3Talpiot Medical Leadership Program, Department of Neurology and the J. Sagol Neuroscience Center, The Chaim Sheba Medical Center, Tel HaShomer, Israel. 4Cellular and Network Physiology Group, Institute of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany. 5CC2 Zentrum für Physiologie, Freie Universität Berlin, Berlin, Germany. 6Experimental Epilepsy Research, Department of Neurosurgery, Neurocenter, University of Freiburg, Freiburg, Germany. 7Developmental Neurobiology, Max Delbrück Center for Molecular Medicine, Berlin, Germany. 8Institute of Biochemistry, University of Cologne and Center for Molecular Medicine, Cologne, Germany. 9Department of Physiology II, University of Freiburg, Freiburg, Germany. 10Sheba Cancer Research Center, The Chaim Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 11BrainLinks-BrainTools, Cluster of Excellence and 12BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany. 13Bernstein Center for Computational Neuroscience Berlin, Berlin, Germany.
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
Barbara Bachtler | Max-Delbrück-Centrum
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
Pollen taxi for bacteria
18.07.2018 | Technische Universität München
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
18.07.2018 | Materials Sciences
18.07.2018 | Life Sciences
18.07.2018 | Health and Medicine