Researchers of Friedrich Miescher Institute for Biomedical Research (FMI) and ETH Zurich implicate a clearly defined neuron type and its circuit in the retina in the pathophysiology of idiopathic congenital nystagmus. In a mouse model of the disease, which shows similar clinical symptoms as patients, a defect in starburst cells elicited by dysfunctional FRMD7 leads to the loss of the horizontal optokinetic reflex.
The eyes of children with idiopathic congenital nystagmus involuntarily move from left to right and back again. Due to this back and forth movement, their vision is severely impaired, some of them are legally blind.
“It was striking to see how we totally lost signal in the horizontal direction in the absence of FRMD7,” commented Michele Fiscella, Postdoctoral Fellow at the FMI and D-BSSE.
In these children, the horizontal optokinetic reflex that usually helps us to hold our gaze steady is lost. In about 70% of the cases the culprit has been identified: a gene sitting on the X chromosome called FRMD7. However, how a defect in this gene leads to the disease has remained unknown.
This is where the work from the group of Botond Roska, Senior group leader at the FMI and Professor at the University of Basel, offers valuable new insights. As they published in Neuron, they showed in mice that the lack of functional FRMD7 causes the loss of the horizontal optokinetic reflex.
More specifically, they could show that the absence of FRMD7 impairs the function of one clearly defined cell type in the retina, the starburst amacrine cells. Starburst amacrine cells are interneurons that asymmetrically inhibit ganglion cells depending on the direction of the movement of an object or the entire scene.
These results were made possible thanks to a microelectronic chip from the group of Andreas Hierlemann from the Department of Biosystems Science and Engineering (D-BSSE) of the ETH Zurich. This high-density array allowed the neurobiologists to measure the electrical signal of thousands of ganglion cells simultaneously, as the retina processed the movement of objects.
“It was striking to see how we totally lost signal in the horizontal direction in the absence of FRMD7,” commented Michele Fiscella, one of the first authors of the publication. “We think that FRMD7 is involved in establishing the asymmetric connections between starburst amacrine cells and ganglion cells, a developmental step occurring early after birth,” said Antonia Drinnenberg, another first author.
With these results, the neurobiologists were for the first time able to implicate a clearly defined neuron type in the pathophysiology of a neurological disease. “To my knowledge this is the first time that we can link a disease to a defect in neurocomputation,” commented Keisuke Yonehara, the lead author of the paper.
To further validate whether dysfunction of FRMD7 in starburst cells could also cause the lack of horizontal reflex in congenital nystagmus in humans, the scientists compared the disease symptoms in patients and in mice lacking FRMD7. “Patients were able to voluntarily move their eyes horizontally, so horizontal eye movement as such was not impaired,” explained Roska, “In addition, the vertical optokinetic reflex was not affected. And since the neuronal pathways controlling the reflex is conserved in mammals, we believe that also in humans the loss of the horizontal reflex is, at least partly, due to the loss of FRMD7 in starburst cells.”
The scientists now have a valuable mouse model at hand that clearly mirrors a symptom of the human disease, and a molecular entry point, FRMD7 in starburst cells, to further probe into the molecular mechanisms of the disease.
Yonehara K*, Fiscella M*, Drinnenberg A*, Esposti F, Trenholm S, Krol J, Franke F, Gross Scherf B, Kusnyerik A, Müller J, Szabo A, Jüttner J, Cordoba F, Police Reddy A, Németh J, Nagy ZZ, Munier F, Hierlemann A, Roska B. (2015) Congenital nystagmus gene FRMD7 is necessary for establishing a neuronal circuit asymmetry for direction selectivity. Neuron,
* These authors contributed equally to this work
Peter Rüegg | ETH Zürich
Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.
The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...
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....
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
20.07.2018 | Power and Electrical Engineering
20.07.2018 | Information Technology
20.07.2018 | Materials Sciences