Researchers uncover the fundamental importance of AMPA receptor biogenesis for brain function
For the first time, Dr. Aline Brechet, Dr. Jochen Schwenk and Prof. Dr. Bernd Fakler, together with geneticists from the University of Leipzig and Paris, France, uncovered the significance of the molecular assembly processes – called biogenesis – of AMPA-type glutamate receptors for proper operation of the human brain.
Schematic illustration of AMPA receptor biogenesis in the endoplasmic reticulum (ER) with subsequent delivery to the synaptic compartment. Upper right: pedigree of one of the discovered FRRS1I families.
Graphics: Bernd Fakler
AMPA receptors, the most abundant neurotransmitter receptors in the brain, are multi-protein complexes that are assembled intracellularly and are subsequently transported to the synapses where they are responsible for signal transduction and information processing. Defective receptor assembly resulting from genetic mutations causes severe intellectual disability with cognitive impairment and epileptic activity.
The results introduce an unexpected mechanism for the control of higher brain functions in humans. The biologists and geneticists recently published their findings in the online-journal Nature Communications.
Using high-resolution proteomic analysis, the scientists identified a population of AMPA receptors in brain membrane preparations that fundamentally differs in their subunit composition from synaptic AMPA receptors. These newly identified complexes are restricted to the endoplasmic reticulum and represent a transitional step in the biogenesis of synaptic receptor complexes.
When formation of these transitional complexes is inhibited via virus administered to rodent brain, the number of synaptic AMPA receptors is drastically reduced. As a result, the researchers detected a largely disturbed synaptic signal transduction.
In the human brain, impairment of AMPA receptor biogenesis may be invoked by mutations in the main subunit of the transitional complexes, the so-called FRRS1I protein. The researchers identified there different FRRS1l mutations in three distinct families where homozygously affected patients (mutations in both, maternal and paternal alleles) suffered from severe brain dysfunction: all patients demonstrated largely impaired intellectual abilities, delayed or complete lack of speech development and epileptic activity.
Interestingly, the diseased brains failed to show any significant alterations in morphology. For the scientists, these observations are indicative for functional deficiencies induced by the impaired AMPA receptor biogenesis as the disease-causing mechanism.
As early as 2012 Fakler’s group has shown that AMPA receptors in the brains are assembled from an array of more than 30 different proteins. Quite a number of these proteins - including the FRRS1I protein - lack annotation of primary function(s). With their current work, the scientists have shown how important these ‘unknown’ protein components and research pursuing their molecular mode of action are for understanding higher brain functions.
The physiologists Jochen Schwenk and Bernd Fakler along with the neurobiologist Aline Brechet conduct research at the Institute of Physiology. Schwenk and Fakler also work at the Cluster of Excellence BIOSS Centre for Biological Signalling Studies at the University of Freiburg.
AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability. A. Brechet, R. Buchert, J. Schwenk, S. Boudkkazi, G. Zolles, K. Siquier-Pernet, I. Schaber, W. Bildl, A. Saadi, C. Bole-Feysot, P. Nitschke, A. Reis, H. Sticht, N. Al-Sanna’a, A. Rolfs, A. Kulik, U. Schulte, L. Colleaux, R. Abou Jamra and B. Fakler (2017) Nature Communications 8, 15910; doi: 10.1038/NCOMMS15910
Prof. Dr. Bernd Fakler
Institute of Physiology, Department II / BIOSS Centre for Biological Signalling Studies
University of Freiburg
Rudolf-Werner Dreier | Albert-Ludwigs-Universität Freiburg im Breisgau
Opening the cavity floodgates
23.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau
Incentive to Move
23.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau
Physicists have developed a technique based on optical microscopy that can be used to create images of atoms on the nanoscale. In particular, the new method allows the imaging of quantum dots in a semiconductor chip. Together with colleagues from the University of Bochum, scientists from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute reported the findings in the journal Nature Photonics.
Microscopes allow us to see structures that are otherwise invisible to the human eye. However, conventional optical microscopes cannot be used to image...
On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.
We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...
What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...
For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.
Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...
At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.
No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...
08.01.2018 | Event News
11.12.2017 | Event News
08.12.2017 | Event News
23.01.2018 | Earth Sciences
23.01.2018 | Life Sciences
23.01.2018 | Materials Sciences