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From molecules to networks: understanding synaptic physiology and pathology of the brain through mouse models

Final Report Summary - EUSYNAPSE (From molecules to networks: understanding synaptic physiology and pathology of the brain through mouse models)

To prepare the ground for the analysis and therapy of neurological and psychiatric disorders, EUSYNAPSE was established as a European research consortium whose focus was on the comprehensive analysis of the molecular mechanisms underlying synaptic information processing. Taking full advantage of the availability of mammalian genome sequences and of the power of mouse genetics it was our goal to develop the mouse as the prime model organism for studying synaptic function. The consortium has brought together scientists who are leading in developing mouse models, resulting in one of the largest collections of synaptic mouse mutants worldwide including strong candidates for disease models. The consortium also united world-leading cell biologists and physiologists in their aim to concentrate on synaptic preparations derived from mice, thus allowing for a combination of molecular perturbation of synaptic function in a single species that was unprecedented so far.

Using an integrated approach at hierarchically increasing levels of complexity, the consortium planned to significantly further our understanding of synaptic function using the mouse as the prime model organism. Based on the ability to manipulate expression levels of synaptic proteins, the role of these proteins in synaptic transmission and in more complex brain functions was expected to be better understood, providing links to human diseases and identifying candidate drug targets for therapeutic intervention in synapse-related brain diseases (synaptopathies).

Excitatory synaptic transmission clearly depends on the variety of function and subcellular localisation of glutamate receptors. Overall this sub-project has contributed significantly to a better understanding of the role of glutamate receptors in synaptic function and plasticity. Knowledge of the precise assembly and of the molecular complexes that underlie proper trafficking and targeting of glutamate receptors is fundamental to understand synaptic modifications during learning-related synaptic plasticity or during pathological forms of changes of synaptic function. Because we think that these mechanisms should ultimately explored in the brain, the work package has provided new tools and methods for the study of receptor trafficking in situ that should be of use to a wide community. A significant outcome of the work by several partners to the work package relies in the original discoveries concerning presynaptic glutamate receptors. This bears important consequences, because we propose that presynaptic ionotropic glutamate receptors are up to now poorly explored targets for interventions in the regulation of synaptic circuits, in the normal and pathological brain. Finally, we have provided links between specific receptor subtypes and forms of synaptic plasticity with behavioural traits by the use of appropriate engineered mouse mutants.

In addition to making significant contributions to our knowledge base on networks in the cortex, olfactory bulb and cerebellum we have also made significant progress in understanding an animal model of autism (VPA). We have also provided new tools for modelling brain function in health and disease and contributed new information about the properties of synapses, computational properties of neurons and the properties of networks. More specifically, we have released a software application called neuroConstuct that enables the automated construction of three-dimensional (3-D) models of neural networks with a high degree of biological detail. This freely available software also provides, for the first time, a simulator independent description of single cell and network models allowing cross-simulator validation, greater interoperability and model transparency. This, together with the development of the related XML language NeuroML, has facilitated standardisation of the description of single cell and network anatomy and the description of kinetic models of ionic conductances and synapses. During this project we have also standardised the statistical approach used to extract quantal parameters with variance –mean analysis.

The project website was set up as planned and is available at http://www.eusynapse.mpg.de. It features a publications database and general information about the project as well. The publishable executive summaries of period one to four can be downloaded. The conferences (EUSYNAPSE meetings) and EUSYNAPSE training offers were announced. An online registration tool was provided for the courses.

The EUSYNAPSE-project, resulted in 78 publications in peer reviewed journals. The collection of scientific publications is available on the EUSYNAPSE website and will be extended as long as project-related papers are released.

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