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The Journal of Neuroscience, June 28, 2006, 26(26):6968-6978; doi:10.1523/JNEUROSCI.1013-06.2006

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Development/Plasticity/Repair
N-Cadherin Transsynaptically Regulates Short-Term Plasticity at Glutamatergic Synapses in Embryonic Stem Cell-Derived Neurons

Kay Jüngling,^1,6 Volker Eulenburg,² Robert Moore,³ Rolf Kemler,³ Volkmar Lessmann,⁴ and Kurt Gottmann^1,5,6

¹Lehrstuhl für Zellphysiologie, Ruhr-Universität Bochum, 44780 Bochum, Germany, ²Department of Neurochemistry, Max Planck Institute for Brain Research, 60528 Frankfurt/Main, Germany, ³Department of Molecular Embryology, Max Planck Institute of Immunobiology, 79108 Freiburg, Germany, ⁴Institut für Physiologie und Pathophysiologie, Johannes Gutenberg-Universität Mainz, 55128 Mainz, Germany, ⁵Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany, and ⁶Institut für Neuro- und Sinnesphysiologie, Heinrich Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany

Correspondence should be addressed to Kurt Gottmann, Institut für Neuro- und Sinnesphysiologie, Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany. Email: Kurt.Gottmann{at}uni-duesseldorf.de

The cell adhesion molecule N-cadherin has been proposed to regulate synapse formation in mammalian central neurons. This is based on its synaptic localization enabling alignment of presynaptic and postsynaptic specializations by an adhesion mechanism. However, a potential role of N-cadherin in regulating synaptic transmission has remained elusive. In this paper, a functional analysis of N-cadherin knock-out synapses was enabled by in vitro neuronal differentiation of mouse embryonic stem cells circumventing the early embryonic lethality of mice genetically null for N-cadherin. In our in vitro system, initial synapse formation was not altered in the absence of N-cadherin, which might be attributable to compensatory mechanisms. Here, we demonstrate that N-cadherin is required for regulating presynaptic function at glutamatergic synapses. An impairment in the availability of vesicles for exocytosis became apparent selectively during high activity. Short-term plasticity was strongly altered with synaptic depression enhanced in the absence of N-cadherin. Most intriguingly, facilitation was converted to depression under specific stimulation conditions. This indicates an important role of N-cadherin in the control of short-term plasticity.

To analyze, whether N-cadherin regulates presynaptic function by a transsynaptic mechanism, we studied chimeric cultures consisting of wild-type neocortical neurons and ES cell-derived neurons. With N-cadherin absent only postsynaptically, we observed a similar increase in short-term synaptic depression as found in its complete absence. This indicates a retrograde control of short-term plasticity by N-cadherin. In summary, our results revealed an unexpected involvement of a synaptic adhesion molecule in the regulation of short-term plasticity at glutamatergic synapses.

Key words: synaptic adhesion molecules; cadherins; synaptic depression; facilitation; retrograde regulation; ES cell-derived neurons

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Received Sept. 24, 2005; revised April 27, 2006; accepted May 19, 2006.

Correspondence should be addressed to Kurt Gottmann, Institut für Neuro- und Sinnesphysiologie, Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany. Email: Kurt.Gottmann{at}uni-duesseldorf.de

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