Function of the synaptic cell adhesion protein neurexin-3 in human neurons
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular and Cellular Neurology and Neuropathology
Final Report Abstract
Our study aimed to dissect the role of neurexin (NRXN) genes in neuronal development and synaptic transmission. Mutations in these synaptic proteins are associated with neuropsychiatric disorders such as autism, schizophrenia, and Tourette syndrome. We generated genetic knockouts for NRXN-1, NRXN-2, and NRXN-3 using CRISPR technology in human stem cells. This approach allowed us to bypass the variability encountered in traditional knockout lines, leading to the creation of polyclonal neurexin knockout cultures. These were then differentiated into induced neurons (iNs) and subjected to detailed analyses of their morphology, synaptic density through immunostaining, and electrophysiological properties via patch clamp recordings. Contrary to our expectations, the deletion of NRXN genes had only limited effects in our observation period, suggesting a potentially limited role of these genes in early development and synapse formation. This suggests the influence of neurexins on neurons may be more subtle and reliant on the biological context than previously understood, highlighting the need for more advanced models to fully grasp their role in brain disorders.
Publications
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Dendritic axon origin enables information gating by perisomatic inhibition in pyramidal neurons. Science, 377(6613), 1448-1452.
Hodapp, Alexander; Kaiser, Martin E.; Thome, Christian; Ding, Lingjun; Rozov, Andrei; Klumpp, Matthias; Stevens, Nikolas; Stingl, Moritz; Sackmann, Tina; Lehmann, Nadja; Draguhn, Andreas; Burgalossi, Andrea; Engelhardt, Maren & Both, Martin
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Microglia integration into human midbrain organoids leads to increased neuronal maturation and functionality. Glia, 70(7), 1267-1288.
Sabate‐Soler, Sonia; Nickels, Sarah Louise; Saraiva, Cláudia; Berger, Emanuel; Dubonyte, Ugne; Barmpa, Kyriaki; Lan, Yan Jun; Kouno, Tsukasa; Jarazo, Javier; Robertson, Graham; Sharif, Jafar; Koseki, Haruhiko; Thome, Christian; Shin, Jay W.; Cowley, Sally A. & Schwamborn, Jens C.
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Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice. Molecular Autism, 13(1).
Wöhr, Markus; Fong, Wendy M.; Janas, Justyna A.; Mall, Moritz; Thome, Christian; Vangipuram, Madhuri; Meng, Lingjun; Südhof, Thomas C. & Wernig, Marius
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Depolarization and Hyperexcitability of Cortical Motor Neurons after Spinal Cord Injury Associates with Reduced HCN Channel Activity. Int J Mol Sci.
Benedetti B., Bieler L., Kreutzer C., Jakubecova D., Benedetti A., Reisinger M., Dannehl D., Thome C., Engelhardt M. & Couillard-Despres S.
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Increased Interhemispheric Connectivity of a Distinct Type of Hippocampal Pyramidal Cells. The Journal of Neuroscience, 44(7), e0440232023.
Stevens, Nikolas Andreas; Lankisch, Katja; Draguhn, Andreas; Engelhardt, Maren; Both, Martin & Thome, Christian
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Live imaging of excitable axonal microdomains in ankyrin-G-GFP mice.
Thome, Christian; Janssen, Jan Maximilian; Karabulut, Seda; Acuna, Claudio; D.’Este, Elisa; Soyka, Stella J.; Baum, Konrad; Bock, Michael; Lehmann, Nadja; Hasegawa, Masashi; Ganea, Dan Alin; Benoit, Chloé Maëlle; Gründemann, Jan; Schultz, Christian; Bennett, Vann; Jenkins, Paul M. & Engelhardt, Maren
