SynSys Project

SynSys stands for ‘Synaptic Systems’. A project funded by the European Commission, SynSys aims at molecular analysis of synapse function and dynamic modeling. The perspective is to generate a blueprint for the discovery of novel pathways and targets that enable rational strategies to design therapies for human brain disease. More information is available on the SynSys website.

Within the Le Novère Lab Martina Fröhlich and Massimo Lai are actively working on the SynSys project. 

Glutamatergic synapses play an important role in learning and memory. Synaptic strength, that is the change in postsynaptic potential after a presynaptic neurotransmitter release, can be varied and is tightly regulated via various intracellular signalling pathways. 

Within SynSys, Martina is establishing a knowledge repository about signalling in the postsynaptic part of the glutamatergic synapse.

This encompasses graphical representations of relevant signalling at different levels of granularity as well as a database in which information can be effectively stored and retrieved. Both maps and database are annotated and link to external sources such as PubMed and UniProt.

A global coarse map provides an overwiew of the processes involved in the glutamatergic synapse. It illustrates the crosstalk between pathways and the existence of various feedback and feedforward loops. In addition, detailed maps for calcium, MAP kinase and phosphoinositide signalling are provided. The collection of maps was generated using a combination of existing knowledge available in public databases such as KEGG and Reactome and was manually curated using scientific literature, the Allen Brain Atlas as well as proteome and interactome data available within SynSys. Both, the maps and the database, are annotated using MIRIAM URIs and link to external sources such as Pubmed, ChEBI and UniProt. The maps were build in CellDesigner and will be available in SBML and SBGN formats.

The maps are used to guide modelling approaches, such as the analyses of crosstalk between various signalling pathways as well as feedback regulation on AMPA and NMDA receptors.

The maps as well as further information are available here.

 

 

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Instead, Massimo's work concerns a smaller subset of pathways, modelled with higher detail. His main focus is the kinase-phosphatase switch that regulates the onset of Long Term Potentiation in hippocampal neurons. A key player in this pathway is calmodulin, a ubiquitous protein that is one of the most important calcium sensors in eukaryotic cells.

A full kinetic model of calmodulin was developed, in order to investigate how the time course of calcium signals affects activity of calmodulin and that of its numerous binding partners within a dendritic spine. The aim is to quantitatively account for calmodulin's observed behaviour as well as the capability of other proteins (in particular Neurogranin, Calcineurin and CaMKII) to affect its calcium affinity and binding kinetics. 

Our goal is to accurately model how the onset of LTP can be fine-tuned by direct regulation of the main calcium sensing molecule.