Role of N- and E-cadherin in the regulation of structural and functional properties at central synapses
Zusammenfassung der Projektergebnisse
Synaptic adhesion molecules are thought to play central roles in transsynaptic signaling during synapse formation, synapse maturation, synaptic refinement processes, and synaptic plasticity. However, although a variety of synaptic adhesion molecules have been characterized at the molecular level, their exact functions in synapse development and physiology are still largely unknown. In this project, we studied the functional roles of classical cadherins, i.e. N- and E-cadherin, at nascent synapses, and during developmental reorganization of synaptic circuitry. We used ES cellderived neurons as a model system to study the consequences of a knockout of the N-cadherin gene, which is embryonically lethal in mice. In addition, we started to use conditional N- and E-cadherin knockout paradigms as a complementary experimental approach. We investigated the molecular mechanisms of vesicle accumulation at nascent synapses using fluorescence imaging and found that N-cadherin expression is required for an efficient clustering of synaptic vesicles at active zones in immature neurons. Furthermore, we discovered that the synaptogenic, vesicle clustering activity of Neuroligin-1 requires the expression of N-cadherin under physiological conditions in immature neurons in both cell cultures and organotypic hippocampal slice cultures. N-cadherin appeared to be crucial for targeting of Neuroligin-1 to nascent synaptic sites, thus resulting in an essential cooperation of these two synaptic adhesion systems. We further studied, whether an asymmetric expression of N-cadherin results in defects in synapse structure and function, thus leading to the well known pre- and postsynaptic matching expression of cadherins at mature synapses in the mammalian brain. To address this, we performed a sparse “rescue” expression of N-cadherin in individual ES-cell derived N-cadherin knockout neurons resulting in presynaptic knockout and postsynaptic expression of N-cadherin. With this type of asymmetric expression of N-cadherin we observed presynaptic dysfunction followed by delayed synapse elimination and axon retraction. Synapse elimination induced by asymmetric cadherin expression might underlie development refinement processes such as retraction of transient axon collaterals in the somatosensory system. We also started to address the functional roles of cadherins other than N-cadherin, e.g. E-cadherin. Using a conditional E-cadherin knockout in cultured cortical neurons, we found defects in GABAergic synaptic transmission that appeared to be caused by an impairment of the formation/stability of a small subset of dendritic GABAergic synapses. In summary, our work revealed important functional roles of members of the cadherin superfamily in synapse formation, early synapse maturation, and synaptic refinement processes during brain development.
Projektbezogene Publikationen (Auswahl)
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(2008). Transsynaptic modulation of the synaptic vesicle cycle by cell adhesion molecules. J. Neurosci. Res. 86: 223-232
Gottmann K
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(2010). Essential cooperation of N-cadherin and neuroligin-1 in the transsynaptic control of vesicle accumulation. Proc. Natl. Acad. Sci. USA 107: 11116-11121
Stan A, Pielarski KN, Brigadski T, Wittenmayer N, Fedorchenko O, Gohla A, Lessmann V, Dresbach T, Gottmann K
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(2011). E-cadherin is required at GABAergic synapses in cultured cortical neurons. Neurosci. Lett. 501: 167-172
Fiederling A, Ewert R, Andreyeva A, Jüngling K, Gottmann K
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(2012). C-terminal fragment of N-cadherin accelerates synapse destabilization by amyloid-β. Brain 135: 2140-2154
Andreyeva A, Nieweg K, Horstmann K, Klapper S, Müller-Schiffmann A, Korth C, Gottmann K
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(2013). Asymmetric N-cadherin expression results in synapse dysfunction, synapse elimination, and axon retraction in cultured mouse neurons. PLoS One 8:e54105
Pielarski KN, van Stegen B, Andreyeva A, Nieweg K, Jüngling K, Redies C, Gottmann K
