Blanc SVSE 4 - Blanc - SVSE 4 - Neurosciences

Planar cell polarity signaling in morphofunctional plasticity of hippocampal synaptic circuits – MossyPCP

Planar cell polarity signaling in morphofunctional plasticity of hippocampal synaptic circuits

The MossyPCP project aims to understand the role of the of the planar cell polarity signaling pathway in the functional wiring and synaptic plasticity of neural circuits under physiological and pathophysiological conditions in mammals.

Understand the role of planar cell polarity (PCP) signaling in the establishment and the plasticity of synaptic circuits

The general aim of our project is to understand the role of planar cell polarity (PCP) signaling in the establishment and the plasticity of synaptic circuits, in physiological and pathophysiological conditions in mammals. <br />Improper formation and maintenance of glutamatergic synapses has a tremendous impact on learning, memory, decision-making and, in general, adaptative behaviour. Growing evidence suggest that PCP signaling is pivotal for brain development, including in mechanisms controlling neuronal migration, neuronal polarity, axonal guidance, dendrite morphogenesis, and asymmetric division, to cite a few. More recent work from our lab also suggests a role for PCP signaling in higher brain functions, but the lack of genetic tools has hampered specific research in adult CNS. <br />

Using Cre-lox technology, we will explore the roles of the PCP signaling in brain development and maturation by specifically deleting Vangl2 in the hippocampus of mice. We will focus our analysis on the morphofunctional maturation and plasticity of mossy fiber synapses in the CA3 region of the hippocampus (Mf-CA3 synapses). Mf-CA3 synapses represent an excellent model for studying the mechanisms of synapse specification and subcellular segregation of glutamate receptors, during development and at a mature stage. The postnatal development of Mf-CA3 synapses follows well-identified morphological and functional maturation landmarks. In addition, Mf-CA3 synapses play a major role in the encoding phase of memory. This system is easily amenable to targeted genetic manipulation of pre- and postsynaptic elements, which can be followed by a precise physiological and behavioral analysis of induced phenotypes.

The project offers a multilevel and multidisciplinary approach to understand the consequences of the disruption of PCP signaling in the hippocampus at a cellular, physiological and behavioural level. We were able to demonstrate that the planar polarity pathway depending on Vangl2 regulates the balance between «pattern completion« and «pattern separation,« two computational processes that are disrupted in the elderly or patient suffering from Alzheimer's.

The final goal of MossyPCP is to show that PCP signaling is not only required for the development of hippocampal networks, but also plays a role in memory. MossyPCP may uncover new roles for PCP modulators as new therapeutics tools to treat synaptopathies and memory pathologies.

Two aspects of our project already provide a realistic prospect of publications.

The general aim of our project is to understand the role of planar cell polarity (PCP) signaling in the establishment and the plasticity of synaptic circuits, in physiological and pathophysiological conditions in mammals.
Improper formation and maintenance of glutamatergic synapses has a tremendous impact on learning, memory, decision-making and, in general, adaptative behaviour. Growing evidence suggest that PCP signaling is pivotal for brain development, including in mechanisms controlling neuronal migration, neuronal polarity, axonal guidance, dendrite morphogenesis, and asymmetric division, to cite a few. More recent work from our lab also suggests a role for PCP signaling in higher brain functions, but the lack of genetic tools has hampered specific research in adult CNS.
Using Cre-lox technology, we will explore the roles of the PCP signaling in brain development and maturation by specifically deleting Vangl2 in the hippocampus of mice. We will focus our analysis on the morphofunctional maturation and plasticity of mossy fiber synapses in the CA3 region of the hippocampus (Mf-CA3 synapses). Mf-CA3 synapses represent an excellent model for studying the mechanisms of synapse specification and subcellular segregation of glutamate receptors, during development and at a mature stage. The postnatal development of Mf-CA3 synapses follows well-identified morphological and functional maturation landmarks. In addition, Mf-CA3 synapses play a major role in the encoding phase of memory. This system is easily amenable to targeted genetic manipulation of pre- and postsynaptic elements, which can be followed by a precise physiological and behavioral analysis of induced phenotypes.
The project will offer a multilevel and multidisciplinary approach to understand the consequences of the disruption of PCP signaling in the hippocampus at a cellular, physiological and behavioural level.

Project coordinator

Madame Nathalie Sans (Université Victor Segalen Bordeaux 2, Neurocentre Magendie, INSERM U862, Team "Planar Polarity and Plasticity") – nathalie.sans@inserm.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

UBordeaux 2 Université Victor Segalen Bordeaux 2, IINS, UMR 5297, Team "Physiology of Glutamergic Synapses "
UBordeaux 2 Université Victor Segalen Bordeaux 2, Neurocentre Magendie, INSERM U862, Team "Pathophysiology of Declarative Memory"
UBordeaux 2 Université Victor Segalen Bordeaux 2, Neurocentre Magendie, INSERM U862, Team "Planar Polarity and Plasticity"

Help of the ANR 598,333 euros
Beginning and duration of the scientific project: November 2012 - 42 Months

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