Neuronal-glia mechanisms in excitatory synapse formation, maintenance and plasticity

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The goal of this Discovery Grant Application is to promote a research program focused on understanding how synapses are formed maintained and remodelled in the CNS. Synapses are key sites of neuronal communication in the brain. They are specialized structures with highly developed molecular machinery which enables chemical neurotransmission. The term synapse was once restricted to pre and postsynaptic neuronal terminals but now we know that non-neuronal cells, in particular astrocytes, also play a role in synaptogenesis, synaptic transmission and plasticity. Recent studies have revealed that astrocytes, once thought to act only as a glue-like structure, show dynamic structural interplay with pre and postsynaptic neuronal terminal of the synapse. The glial cells actively survey their neuronal microenvironment and give feedback to neurons through calcium mediated release of neuroactive substances that regulate synaptic properties. Despite the knowledge of the importance of glia in the brain the understanding of the cellular and molecular mechanisms that underlie communication between neurons and glia is incomplete. In this Discovery Grant proposal we will address several unresolved issues with respect to astrocyte-synapse structural and signalling mechanism in dendritic spine formation, stability and remodelling. First we will determine how early GABA transmission controls astrocytic tiling using transgenic animals, electrophysiology, molecular biology and high resolution confocal microscopy techniques. Next we will investigate the importance of glial calcium signalling in dendritic spine-remodelling. Finally we will investigate glial neuronal structural interplay during activity-dependent synaptic remodelling. This Discovery Grant project will provide an excellent conceptual and technical training for students interested in understanding brain circuitry. It is envisaged that data produced by these students will also create novel insights into glial-neuronal interactions and mechanisms that control excitatory synapse formation, activity and plasticity.