Cooperation of synaptic adhesion molecules in synapse formation and function
Final Report Abstract
Chemical synapses releasing neurotransmitter for communication between nerve cells are crucial for brain function. Synaptic cell adhesion molecules (SCAMs) play important regulatory roles in transsynaptic signaling during synapse formation, synapse maturation, synaptic refinement processes, and synapse function and plasticity. A diversity of synaptic adhesion molecules have been characterized at the molecular level, however, their exact functions in synapse formation and physiology are still largely unclear. In this project, we studied the functional roles of the classical cadherin N-cadherin in immature and mature, functional synapses. As an experimental paradigm, we used a “loss-of-function” conditional N-cadherin knockout approach in combination with a “gain-offunction” Neuroligin1 and N-cadherin overexpression approach. At immature and at maturating synapses in cultured neurons from fetal mouse neocortex, we studied the functional cooperation of N-cadherin and Neuroligin1 required for the synaptogenic activity of Neuroligin1. We obtained evidence that N-cadherin is important for targeting of Neuroligin1 to synaptic sites, thus resulting in an essential cooperation of these two synaptic adhesion systems. With increasing functional maturation of synapses in vitro, the synaptogenic effect of Neuroligin1 overexpression was strongly reduced. In parallel, we observed strong maturational changes in N- cadherin expression at the periphery of excitatory glutamatergic synapses using innovative superresolution microscopy. This points to the idea, that the molecular cooperation of N-cadherin and Neuroligin1 might be strongly dependent on the maturational state of synapses. We also investigated whether other strongly synaptogenic SCAMs (such as LRRTM2) functionally depend on cooperation with N-cadherin. However, we observed that the synaptogenic effect of LRRTM2 was independent of N-cadherin expression, indicating that the requirement for cooperation with N-cadherin is a specific feature of Neuroligin1. Unexpectedly, using both N-cadherin knockout and overexpression, we observed that N-cadherin has an important regulatory role in synaptic vesicle endocytosis to maintain the synaptic vesicle pool for transmitter release at mature, functional synapses. In summary, this project revealed a dual functional role of N-cadherin in both, early synapse maturation and in mature synapse function.
Publications
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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
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(2017). Release activity-dependent control of vesicle endocytosis by the synaptic adhesion molecule N-cadherin. Sci Rep 7: 40865
van Stegen B, Dagar S, Gottmann K
