"Communication between neurons in the brain occurs mainly via chemical synapses. Activity-dependent changes in synaptic strength represent the cellular basis of learning and memory and depend on both the presynaptic terminal and the postsynaptic specialization. Although postsynaptic strength and presynaptic transmitter release have been extensively studied in isolation, simultaneous investigation of pre- and postsynaptic potentiation at spine synapses is still a technical challenge. The laboratory of Thomas Oertner recently established a method to optically identify and resolve the pre- and postsynaptic components of functional synapses in live tissue. The applicant will exploit and further refine this technique by combining optogenetic methods to manipulate electrical activity in the pre- and postsynaptic neurons with high-resolution imaging of structural plasticity and two-photon calcium imaging. As this all-optical approach is non-invasive it permits the investigation of the coordination of pre- and postsynaptic plasticity (transsynaptic matching) over extended time periods. With this new method the applicant wishes to study the precise temporal and molecular processes which control transsynaptic matching at a structural and functional level. As a second step the applicant intends to unravel possible retrograde signals mediated by diffusible retrograde messengers and transsynaptic cell-adhesion molecules. For this he will selectively manipulate individual components of transsynaptic signalling systems at the pre- or postsynaptic side using pharmacological (e.g. selective inhibitors) and genetic tools (shRNA and knock-out animals)."