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
Researchers discover vaccine to strengthen the immune system of plants
24.01.2020 | Westfälische Wilhelms-Universität Münster
Brain-cell helpers powered by norepinephrine during fear-memory formation
24.01.2020 | RIKEN
Researchers from Dresden and Osaka present the first fully integrated flexible electronics made of magnetic sensors and organic circuits which opens the path towards the development of electronic skin.
Human skin is a fascinating and multifunctional organ with unique properties originating from its flexible and compliant nature. It allows for interfacing with...
Researchers of the Carl Gustav Carus University Hospital Dresden at the National Center for Tumor Diseases Dresden (NCT/UCC), together with an international...
A Duke University research team has identified a new function of a gene called huntingtin, a mutation of which underlies the progressive neurodegenerative...
For years, a new synthesis method has been developed at TU Wien (Vienna) to unlock the secrets of "strange metals". Now a breakthrough has been achieved. The results have been published in "Science".
Superconductors allow electrical current to flow without any resistance - but only below a certain critical temperature. Many materials have to be cooled down...
KIT researchers develop novel composites of DNA, silica particles, and carbon nanotubes -- Properties can be tailored to various applications
Using DNA, smallest silica particles, and carbon nanotubes, researchers of Karlsruhe Institute of Technology (KIT) developed novel programmable materials....
16.01.2020 | Event News
15.01.2020 | Event News
07.01.2020 | Event News
24.01.2020 | Life Sciences
24.01.2020 | Life Sciences
24.01.2020 | Life Sciences