Final Report Summary - ACTIVE_NEUROGENESIS (Activity-dependent signaling in radial glial cells and their neuronal progeny)
A fundamental question in neuroscience is how nerve cells are generated and directed to form functional groups of interconnected cells. During development all of these nerve cells (‘neurons’) must be born and it is clear that some cells, referred to as progenitor cells, give birth to neurons by successively dividing. The resulting neurons then establish their mature properties and form synaptic connections with specific sets of other cells. Understanding how neurons form these connections is intimately linked to understanding how neurons are born in the first place. This project has established methods for observing, in real time, the morphology and functional properties of neuronal progenitor cells, and the neurons that they give rise to, in an intact vertebrate nervous system. The visual system of the Xenopus Laevis tadpole offers excellent and non-invasive optical access to the brain, making in vivo time-lapse imaging feasible over the timescale of minutes to weeks. This research project has used this experimental system, and other experimental systems, to examine a series of fundamental questions about neuronal progenitor cells and their neuronal progeny. One achievement since the start of the project has been the development of methods for investigating signalling processes in neuronal progenitors and differentiated neurons. A particular focus has been on how dynamic changes in the concentration of ions inside these cells could influence their behaviour. A related achievement has been an examination of how these cells use chemical and ionic signals to regulate either their behaviour or their differentiation as neurons. As part of this work, the project has established how quickly progenitor cells divide, when progenitor cells switch their behaviour to start producing different types of neuron and the mechanisms by which neurons establish synaptic connections with one another. One unexpected discovery was that at early stages of brain development, injured neuronal progenitors can initiate waves of calcium activity that trigger contractions of the brain tissue. This is the first description of physical contractions in the developing brain. Furthermore, we went on to show that these contractions serve to expel the damaged cell, which protects the remaining healthy tissue from further damage. Another important achievement during the project has been our investigations into how neurons form synaptic connections with one another and how these are influenced by genetic and environmental factors. Our studies have revealed that neurons connect to one another in a manner that reflects the progenitor cells from which they are derived. More specifically, clonally related neurons that are born from the same progenitor cell form part of the same sub-network of neurons and exhibit common response properties in vivo. Finally, the project has generated a series of studies that have examined early synaptic communication. This has focussed on GABAergic signalling, which is known to exhibit distinct features in the developing brain due to high intracellular chloride levels. In summary, the major achievements over the course of the project include the successful establishment of a research group that is examining fundamental aspects of neuronal development, new methods for investigating activity-dependent signalling during neural development, and the identification of novel processes by which neural progenitors and developing neurons signal with one another to establish functionally mature neuronal circuits.