Cycle 4 project 2

Nanoscale imaging of the tripartite synapse in vivo

 

Mirelle-ter-VeerPhD student: Mirelle ter Veer, Netherlands
Home Institute: Bordeaux Neurocampus; Principle Investigator: Valentin Nägerl
Host Institute: Neuroscience Center Zürich; Principle Investigator: To be defined
2nd Host Institute: European Neuroscience Institute Göttingen; Principle Investigator: Detlev Schild

Executive Summary

Research on glia cells, in particular astrocytes in the brain, has in recent years led to a thorough reappraisal of their role for brain function, extending greatly beyond the classic view as mere providers of structural and nutritional support to neurons. The concept of the “tripartite synapse”, composed of neuronal and astrocytic elements, recognizes the important role that astrocytes are thought to play for regulating information transfer at synapses in the central nervous system in a highly dynamic and multifaceted way.

However, our understanding of how astrocytes communicate with neurons and synapses is still very fragmented. For instance, we really don’t know much about the morphological organization of the tripartite synapse, how variable and dynamic it is. Likewise, we are mostly in the dark about how glial coverage shapes synaptic transmission and (structural) plasticity.

Progress on these basic questions is impeded by a number of serious experimental challenges: Firstly, astrocytes have an enormously complex morphology and their distal processes that ensheath synapses are very small, rendering them hardly accessible to traditional light microscopic approaches.

Hence, most of what we know about the morphology of the tripartite synapse derives from electron microscopy, which is problematic because of fixation artifacts and which cannot dissect dynamic events in a physiological setting.

Secondly, the fact that astrocytes are key conduits for neuro-vascular coupling, regulating the flow of oxygen and glucose from blood to neurons in response to changes in neural activity, means that reduced experimental preparations like cultured neurons and even brain slices will ultimately prove inadequate for a clear understanding of astrocyte-synapse physiology.

Hence, there is a need to develop imaging approaches that have sufficient spatial resolution and that are compatible with in vivo brain preparations.

To meet these challenges and investigate the structure and function of the tripartite synapse under realistic experimental conditions, we propose to develop a novel approach based on a powerful combination of in vivo superresolution STED microscopy, in vivo two-photon Ca2+ imaging, pharmacology and molecular genetics. We aim to investigate tripartite synapse structures in layer 1 of the mouse neocortex, which is a key layer for integration of sensory inputs and intracortical activity and which is accessible for both in vivo two-photon and STED microscopy.

The project is based on a collaboration between the teams of Valentin Nägerl (Bordeaux) and Fritjof Helmchen (Zürich), providing strong complementary expertise in superresolution STED microscopy of synapses and glia cells in brain slices and in vivo two-photon Ca2+ imaging and cortical network function, respectively. In addition, Mark Verheijen (Amsterdam), an expert on glia-neuron interactions, will strengthen the molecular and signaling aspects of the project, providing guidance and technical assistance where necessary.

Expanding from the methodological state-of-the-art, the project has a very high potential for original discoveries and significant conceptual advances regarding the role of the tripartite synapse in the living brain. Moreover, our project will lead to new opportunities to study neuron – glia interactions in combination with tools of molecular genetics and in the context of animal models for neurological diseases.

 

 

 

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