Contribution of IP3Rs and endoplasmic reticulum to Ca2+ signalling in astrocytes – CASTRO

Research on glia cells, in particular astrocytes in the brain, has in recent years led to a thorough reappraisal of their role for brain functions, 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 play for regulating information transfer at synapses in the central nervous system in a highly dynamic and multifaceted way.
Despite much progress, the cellular and molecular substrates underlying the crosstalk between astrocytes and neurons at synapses remained to be characterized. One of the major limitations to investigate such interactions is the enormous morphological complexity and small size of astrocytes. This is particularly true for distal astrocytic processes that contact synapses, which typically are much too small to be properly resolved by conventional light microscopy. Thus, most of what we know about the structure of the tripartite synapse derives from electron microscopy, which is problematic because of fixation artifacts and which is poorly suited for dissecting dynamic events in a physiological setting.
Enabled by a novel and powerful combination of live-cell STED imaging, electrophysiology, function-blocking antibody and targeted genetic deletion using hippocampal brain slices, the project CASTRO aims to substantially advance our understanding of the functional interactions between astrocytes and neurons at synapses. It will address several fundamental questions about the role of the different inositol triphosphate receptors (IP3R) subtypes and the endoplasmic reticulum mechanism in astroglial Ca2+ signalling and gliotransmission under realistic experimental conditions.
Our proof-of-principle experiments clearly demonstrate that it is possible to specifically target IP3R subtypes in individual astrocytes and perform nanoscale imaging of astroglia in living brain slices. The project brings together two teams with outstanding track records in the fields of astrocyte physiology and gliotransmission as well as synaptic plasticity and super-resolution imaging. Because of synergistic effects, the partners are well positioned to propose this project, which lies at the forefront of current neuroscience research, both in terms of theme and methods. The unique combination of strengths ensures that the consortium can have a significant impact in a fiercely competitive field, providing an opportunity for both teams to advance their research agendas and to reinforce their leadership positions at the international level.