The key scientific question addressed by the present work is how synapse development and synaptic activity are mechanistically coupled in vivo. Our results led to the discovery of a bidirectional mechanism, whereby Hebbian synaptic plasticity guides growth of postsynaptic receptor fields and sparse transmitter release controls the stabilization of their molecular composition.

By employing Optogenetics at the glutamatergic Drosophila neuromuscular junction to evoke activity in vivo, we found out that correlated pre- and postsynaptic activation led to subunit specific incorporation of GluR-IIA-type glutamate receptors into postsynaptic densities (PSD), thus increasing postsynaptic sensitivity. Conversely, the same receptor type was rapidly removed from PSDs when receptor activation did not cause substantial postsynaptic depolarization.

In a previous in vivo imaging study it was demonstrated that nascent synapses grow by incorporating GluR-IIA. Conversely, mature synapses put a break on further IIA recruitment (Schmid et al., 2008). Here, we put forward a comprehensive model, which explains how these two phenomena are controlled by activity. In addition, our data provide an elegant mechanism to control Hebbian plasticity by using spontaneous transmitter release as a negative regulator of synapse growth.

Schmid, A., Hallermann, S., Kittel, R.J., Khorramshahi, O., Frölich, A.M., Quentin, C., Rasse, T.M., Mertel, S., Heckmann, M., and Sigrist, S.J. (2008). Activity-dependent site-specific changes of glutamate receptor composition in vivo. Nat Neurosci 11, 659-666.