Previously unknown function: Noelin proteins central for learning ability in mammalian brains

A German-American research team headed by Prof. Dr. Bernd Fakler from the Faculty of Medicine at the University of Freiburg demonstrated the major influence of Noelin1-3 proteins on learning and memory formation in the mammalian brain. The results of this detailed study were recently published in the journal Neuron by the publisher Cell Press. The lead authors are Dr. Sami Boudkkazi and Dr. Jochen Schwenk, both members of the Institute of Physiology in Freiburg, and Dr. Naoki Nakaya from the National Institutes of Health in Bethesda, Maryland, USA.

Better understanding of the brain established

At least 40 proteins are required for the assembly and function of AMPA receptors, the main neurotransmitter receptors in excitatory synapses of the brain. In the past ten years, Fakler’s research group has elucidated the functional significance of the majority of these building blocks; however, the function of some building blocks still remained unresolved. These unknown proteins included Noelins1-3, a family of secreted proteins highly conserved in all vertebrates.

“We have investigated AMPA receptors in the brains of mice with targeted deletions of the Noelin1-3 proteins. These knock-out animals were generated by our American partners led by Dr. Stanislav Tomarev from the National Institutes of Health, Bethesda, Maryland, USA,” says study leader Fakler. He summarizes the main results as follows: “We show that Noelins, assembled as tetramers, link AMPA receptors to a variety of anchor proteins including neurexin1 or neuritin1, thus stabilizing the receptors in the cell membrane. Noelins1-3 are responsible for establishment of the activity-dependent synaptic plasticity of nerve cells: they operate as ‘universal anchors’ that control the distribution and dynamics of AMPAR receptors in the brain.”

These results not only promote the conclusion that in the absence of Noelins synapses are hardly able to undergo learning. Additionally, the absence of these secretory proteins exerts profound negative effects on both function and morphology of neurons on the longer term. "Our work shows that the complexity of neurons decreases and that some functions are no longer possible. What consequences these changes may have on higher brain function(s) remains to be seen," Fakler says.

Findings fundamental for basic research in other disciplines

The results of this international research efforts may not entirely apply to the human brain, Fakler says. “We assume, however, that AMPA receptors are almost identical between rodents and humans. So I’m optimistic that our findings on Noelin action(s) in the rodent brain may well contribute to basic research in humans.” In addition, scientists from other disciplines may use our results to explain the variable degree of plasticity observed between neurons or to draw conclusions on operation of neural networks and their information processing.

• Original publication: Sami Boudkkazi, Jochen Schwenk, Naoki Nakaya, Aline Brechet, Astrid Kollewe, Harumi Harada, Wolfgang Bildl, Akos Kulik, Lijin Dong, Afia Sultana, Gerd Zolles, Uwe Schulte, Stanislav Tomarev, Bernd Fakler. A Noelin-organized extracellular network of proteins required for constitutive and context-dependent anchoring of AMPA-receptors, In: Neuron (2023). https://doi.org./10.1016/j.neuron.2023.07.013
• Prof. Dr. Bernd Fakler is Director of the Institute of Physiology at the Faculty of Medicine at the University of Freiburg and Area Coordinator in the Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling Studies. His research interests include the molecular organisation and function of rapid signal transduction at the cell membrane, proteomic analysis of membrane protein complexes, and structure-function analysis of ion channels and G-protein coupled receptors. Websites: www.cibss.uni-freiburg.de/de/ueber-cibss/forschende/translate-to-deutsch-person-details/prof-dr-bernd-fakler and www.med.uni-freiburg.de/de/fakultaet/profs/fakler
• The study Molecular Analysis of Excitatory Neurotransmission was developed within the project Molecular Analysis of Assembly and Function of AMPA-Receptor Complexes in the Plasma Membrane of Mammalian Brain Neurons, ID 439189341 and was funded by the German Research Foundation (DFG).

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