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Molecular mechanisms contributing to synaptogenesis in hippocampal slice cultures

English title Molecular mechanisms contributing to synaptogenesis in hippocampal slice cultures
Applicant Muller Dominique
Number 105721
Funding scheme Project funding (Div. I-III)
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2004 - 30.09.2009
Approved amount 1'128'333.00
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Keywords (7)

Synaptic plasticity; synaptogenesis; development; mental retardation; hippocampus; excitatory transmission; learning and memory

Lay Summary (English)

Lead
Lay summary
The objectives of the project were to investigate the mechanisms regulating synapse formation and dynamics in the developing hippocampus. Previous work from our as well as other laboratories has shown that neuronal activity can trigger the formation of new spines and synapses and that synaptic contacts undergo a continuous turnover and replacement. Many issues however regarding how synapses are formed and stabilized and what molecules contribute to these processes remained unclear. This is important because many recent studies suggest that genetic alterations of synaptic proteins implicated in these processes of synapse formation and plasticity could be responsible for developmental diseases such as mental retardation or autism spectrum disorders. To address this, we used organotypic slice cultures as a long-term model and repetitive 2-photon confocal imaging combined to 3D EM reconstructions and transfection approaches. Our results revealed the specific role of the mental retardation proteins PAK3 and ARHGEF6 in altering synapse morphology and synapse formation and plasticity mechanisms. We also uncovered a new function of nitric oxide produced by postsynaptic cells to promote the differentiation of axons into terminals and the formation of synaptic contacts. Finally we showed that specific patterns of activity that trigger synaptic plasticity resulted in a lasting increase in spine turnover, promoting the long-term stabilisation of stimulated synapse, while in contrast leading to the replacement of non-stimulated spines by new ones. These results revealed a new selection mechanism contributing to the formation of specific synaptic networks during development and provide new tools to better understand how genetic defects implicated in developmental diseases could alter the properties and functioning of synaptic networks.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Employees

Associated projects

Number Title Start Funding scheme
56852 Activity-induced synaptogenesis in hippocampal organotypic cultures 01.10.1999 Project funding (Div. I-III)
127552 Molecular control of spine dynamics in hippocampal slice cultures 01.10.2009 Project funding (Div. I-III)

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