Role of the Coxsackievirus and Adenovirus Receptor CAR in Synaptic Transmission and Memory Formation

• Applicant: Professor Dr. Michael Gotthardt
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 313912461

Final Report Abstract

The coxsackievirus and adenovirus receptor (CAR) is a cell adhesion protein and was originally identified as a virus-receptor for human pathogens such as CVB3. Its physiological function in the postnatal brain is still largely unknown. Nevertheless, the elevated prenatal expression of CAR in heart and brain implicates a function of CAR in embryonic development. During the last years the function of CAR was primarily studied in the heart. In mice with CAR deficiency hearts were malformed and cardiac bleeding led to early embryonic lethality. Inducible heart specific CAR knockout mice (KO) were viable and appeared normal, but showed an impaired electrical conduction in the heart. This phenotype was associated with changes of gap-junctions - specialized cell-cell contacts formed by connexins. Using two brain specific CAR knockout mice (KO), we discovered an unexpected role of CAR in neuronal communication. This includes increased basic synaptic transmission at hippocampal Schaffer collaterals, resistance to fatigue, and enhanced long-term potentiation. Spontaneous neurotransmitter release and speed of endocytosis are increased in KOs, accompanied by increased expression of the exocytosis associated calcium sensor synaptotagmin 2. Using proximity proteomics and binding studies, we link CAR to the exocytosis machinery as it associates with syntenin and synaptobrevin/VAMP2 at the synapse. Increased synaptic function does not cause adverse effects in KO mice, as behavior and learning are unaffected or increased – depending on the mouse strain. Thus, unlike the connexin-dependent suppression of atrioventricular conduction in the cardiac knockout, communication in the CAR deficient brain is improved, suggesting a role for CAR in presynaptic processes. These results point towards a role of CAR in the presynaptic aspect of neuronal signal transduction which makes CAR a relevant therapeutic target for neurological diseases with impaired signal transduction.

Publications

• (2018) Microtubule cytoskeleton regulates connexin 43 localization and cardiac conduction in cardiomyopathy caused by mutation in A-type lamins gene. Human Molecular Genetics 28 (24): 4043-4052
  Macquart, C., Jüttner, R., Le Dour, C., Chatzifrangkeskou, M., Schmitt, A., Gotthardt, M., Bonne, G. and Muchir, A.
  
• (2019) The cell adhesion protein CAR is a negative regulator of synaptic transmission. Scientific Reports 9: 6768
  Wrackmeyer, U., Kaldrack, J., Jüttner, R., Pannasch, U., Gimber, N., Freiberg, F., Schmitz, D., Haucke, V., Rathjen, F.G. and Gotthardt, M.
  
• (2021) Defective metabolic programming impairs early neuronal morphogenesis in human neural cultures and brain organoids of Leigh syndrome. Nature Communications 12: 1929
  Inak, G., Rybak-Wolf, A., Lisowski, P., Jüttner, R., Zink, A., Mlody, B., Glazar, P., Secker, C., Ciptasari, U. H., Stenzel, W., Hahn, T., Diecke, S., Priller, J., Gotthardt, M., Kühn, R., Wanker, E. E., Rajewsky, N., Schuelke, M., Prigione, A.