D16 - Schuster

In recent years it has become increasingly clear that ionotropic neurotransmitter receptors participate not only in postsynaptic signal transmission, but they are also localized in presynaptic membranes affecting the release of presynaptic vesicles. However, apart from the principal identification of presynaptic ionotropic transmitter receptors almost all mechanistic aspects of their functional regulation, their function and their involvement in synaptic development remain elusive. During our recent analysis of  experience-dependent potentiation and the developmental role of presynaptic NMDA-receptors (NMDARs) at larval neuromuscular junctions (NMJs) of Drosophila we discovered, that these receptors are un-silenced by a retrograde nitric oxide (NO) signaling pathway, whose activation appears to be mandatory to initiate NMDAR-mediated synaptic potentiation. We have therefore focused on the functional analysis of synaptic NO-synthase (NOS) and made three unexpected observations: (1) blocked postsynaptic NOS-activity suppresses the synaptic localization of the Drosophila homologue of PSD-95, the synaptic scaffolding protein DLG; (2) a Calcineurin/PKA-mediated shift in the functional balance of postsynaptic glutamate receptors is required to activate presynaptic NMDARs; (3) the unconventional Myosin VIIa Crinkled, a homologue of a prominent Usher Syndrome gene in humans, restricts the postsynaptic activity of PKA and thereby seems to be involved in the regulation of the functional balance of postsynaptic glutamate receptors. Based on these findings it is tempting to speculate that postsynaptic Myosin VIIa, PKA and Calcineurin cooperate in the regulation of postsynaptic glutamate receptor properties thereby controlling the activity of postsynaptic NOS and consequently the postsynaptic localization of the scaffolding protein DLG/PSD-95 and the retrograde activation of presynaptic NMDARs. Such a regulatory system could provide a high degree of local specificity during functional and morphological synaptic changes throughout development.

In order to assess, whether the above hypothesis could apply to the development and plasticity of the glutamatergic synapses of Drosophila NMJs or whether the identified molecules use alternative strategies to control the synaptic connectivity in this system we will follow three lines of experiments: (1) our recent results suggest that NO-signaling plays a central coordinating role in the structural and functional organization of glutamatergic synapses. We will therefore first characterize the synaptic NOS-activity profile and its regulation during development and experience-dependent plasticity. (2) We will also characterize the physical and functional interaction of NOS and DLG and its consequences on the localization and function of other synaptic molecules. (3) We will then attempt to characterize the role of the unconventional Myosin VIIa during these postsynaptic signaling events throughout development.

Während der Entwicklung neuronaler Netzwerke greifen genetisch vorprogrammierte und nutzungsabhängige Prozesse ineinander, um in einer präzisen und dennoch dynamischen synaptischen Verschaltung von Neuronen zu resultieren. An den sich entwickelnden neuromuskulären Endplatten (NMEs) von Larven der Taufliege Drosophila lassen sich solche Prozesse mit hoher Auflösung untersuchen. Da unsere Vorarbeiten gezeigt haben, daß die NO-Synthase (NOS) eine zentrale Rolle sowohl in der funktionellen Regulation präsynaptischer NMDA-Rezeptoren, als auch in der synaptischen Lokalisierung des postsynaptischen scaffolding Proteins DLG (PSD-95 Homolog) spielt, wird dieses Projekt die Prozesse untersuchen, die der funktionellen NOS-Regulation und deren Konsequenzen zugrunde liegen.

Own project-related publications since the last application (2005)

Schuster, C. M. (2006). Glutamatergic synapses of Drosophila neuromuscular junctions: a high-resolution model for the analysis of experience-dependent potentiation. Cell Tissue Res 326, 287-299.

Steinert, J. R., Kuromi, H., Hellwig, A., Knirr, M., Wyatt, A. W., Kidokoro, Y., and Schuster, C. M. (2006). Experience-dependent formation and recruitment of large vesicles from reserve pool. Neuron 50, 723-733.

Own project-related publications (submitted / in preparation)

Steinert, J. R., Wyatt, A.W., Heindorf, M., Litzenburger, U., Wismar, J., Schmitt, B., Kuzin, B., Enikolopov, G., and Schuster, C.M. (2007). Retrograde Nitric Oxide Signaling Activates Presynaptic NMDA Receptors. Neuron, under revision.

Steinert, J. R., Knirr, M., Litzenburger, U., and Schuster, C.M. (2008). Experience-Dependent Regulation of the Functional Balance of Postsynaptic GlutamateReceptors. to be submitted.

Marella, S., Steinert, J.R., Cheney, C., Knirr, M., and Schuster, C.M. (2008) The unconventional myosin VIIa Crinkled controls postsynaptic glutamate receptor activity and retrograde signalling at Drosophila NMJs. in preparation.

Selected publications from other projects outside the SFB since 2005

Schwenkert, I., Eltrop, R., Funk, N., Steinert, J.R., Schuster, C.M., and Scholz, H. (2008). The hangover Gene Negatively Regulates Bouton Addition at the Drosophila Neuromuscular Junction. Mech.Dev, in press.

Christoph Schuster

Interdiziplinäres Zentrum für

Neurowissenschaften (IZN)

Apt. Neurobiologie, Universität Heidelberg

Im Neuenheimer Feld 345

69120 Heidelberg

Phone:  06221-548300
Fax:      06221-544496
Email:    Schuster(at)nbio.uni-heidelberg.de