Calcium signals during early development: experiments and theory

After neuronal migration, neuronal circuit formation during early brain development is dominated by extensive dendritic outgrowth and synapse generation. The formation of circuits is dependent on neuronal activity patterns based on sensory experience depending on extrinsic cues and intrinsically generated spontaneous activity. Critical periods are usually defined as developmental windows when deprivation from sensory experience has an impact on cortical sensory representations. During so-called precritical periods, a comparatively strong influence of spontaneous intrinsically generated activity patterns has been demonstrated (Feller and Scanziani, 2005). In neonatal rodents, intrinsically generated spontaneous and synchronized global neuronal network events occur. The time frame for these events generally depends on the brain region, usually with a peak in the first postnatal week. In this period, spontaneous synchronized events are modulated by sensory inputs to varying degrees in different systems (Khazipov and Luhmann, 2006). These activity patterns contribute to neuronal circuit formation through the generation and elimination of axons, dendrites, spines and synapses (Ben-Ari, 2001). However, how electrical input is transmitted into biochemical signaling mediating structural plasticity is still under investigation. One key player is Ca2+, since it can serve as both, electrical charge carrier at the membrane and biochemical second messenger in intracellular signaling cascades (Hille, 2001). The dynamics of Ca2+ concentration plays a key role in a multitude of cellular processes and is a phenomenon highly variable in its appearance in space and time. Cytosolic Ca2+ levels are modified by the coordinated release from intracellular stores located in cell organelles, particularly the endoplasmic reticulum (ER). Receptor channels in the ER membrane, such as inositol trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs), mediate complex Ca2+ transients in response to binding of specific ligands including Ca2+ to binding sites on the cytosolic side of the channels. Once Ca2+ is released it diffuses into the cytosol and increases the open probability of neighboring channels by binding to activating sites on the channel protein. This provides a self-amplifying mechanism called Ca2+ induced Ca2+ release (CICR), which is crucial for the generation of spatio-temporal waves (Berridge, 1998). Indeed, neuronal plasticity and circuit formation have been shown to depend on cytoplasmic Ca2+ elevations, which are necessary for dendritic and filopodial outgrowth as well as spine formation. We recently demonstrated that Ca2+ release from intracellular stores via RyRs is able to generate signaling nanodomains involved in plasticity of dendritic spines (Johenning et al., 2015). Now, as a next step towards understanding the role of calcium in neuronal plasticity we will investigate the functional interaction between Ca2+ signals arising from the plasma membrane as well as from intracellular store release and spine formation during postnatal development. In a multidisciplinary experimental and theoretic approach to study highly complex phenomena such as Ca2+ wave generation and propagation into spines we will identify how Ca2+ signals govern the development of neonatal circuits at different spatial scales.