Cycle 2 project 1

Project 1: The role of DLG-MAGUKs as signaling scaffolds for linking modulatory neurotransmitter systems to long-term synaptic plasticity

PhD student: Plinio Das Neves Favaro, Brazil
Home Institute: European Neuroscience Institute Göttingen; Principle Investigator: Oliver Schlüter
Host Institute: Bordeaux Neuroscience – Université Bordeaux Segalen; Principle Investigator: Christophe Mulle

Executive Summary
PSD-93, PSD-95, SAP97 and SAP102 constitute the family of DLG-MAGUKs. PSD-95 is the prototypic signaling scaffold of the postsynaptic density (PSD), with around 300 copies per single synapse. Six protein-protein interaction modules mediate the interaction of PSD-95 to glutamate receptors, cell-adhesion molecules, signaling molecules, self-multimerization and other scaffold components of the PSD. We and others have shown that PSD-95 is essential for some forms of long-term synaptic plasticity (a potential cellular correlate of learning and memory) by linking NMDA receptor activation to downstream signaling events.

PSD-95 and other DLG-MAGUKs are directly or indirectly involved in several psychiatric disease mechanisms. In their central position in the PSD, DLG-MAGUKs directly interact with disease related gene products, including Neuroligin, Neurexin and Shank3 in autism spectrum disorders and SAPAP3 in obsessive-compulsive disorder. Furthermore, a direct role of DLG-MAGUKs in schizophrenia was suggested as studies have shown that PSD-95 and PSD-93 protein levels are changed in postmortem studies of affected schizophrenia patients, and mutations in the PSD-93 gene have been identified to be associated with some schizophrenia cases.

Recent evidence has shown that PSD-95 is involved in modulatory neurotransmitter systems. Both dopamine and noradrenaline receptors can directly interact with PSD-95. Our preliminary studies have suggested that this interaction might be important for the permissive role of these modulatory neurotransmitter systems in synaptic plasticity. Catecholamine systems have been the primary target for psychiatric disorders, suggesting their critical role in modulation of synaptic plasticity that consequently contribute to the etiology of psychiatric disorders.

We have developed an extensive toolbox in manipulating DLG-MAGUKs, including genetically engineered mouse lines, viral mediated gene transfer to study the functional roles of these proteins in regulating synaptic transmission and plasticity. The objective of this project is to determine the mechanisms, how different DLG-MAGUKs link catecholaminergic signaling to modulate long-term synaptic plasticity. We hypothesize, that DLG-MAGUKs centrally scaffold catecholaminergic receptors and their downstream signaling molecules, such as protein kinases and effector molecules to locally enable the signaling event. Furthermore, different isoforms and family members of the DLG-MAGUKs might determine the specificity of these signaling complexes together with neuron-type specific expression of catecholaminergic receptors.