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The calcium ion (Ca2+) is an essential second messenger that plays a pivotal role in neurogenesis. In the ventricular zone (VZ) of the neocortex, neural stem cells linger to produce progenitor cells and subsequently neurons and glial cells, which together build up the entire adult brain. The radial glial cells, with their characteristic radial fibers that stretch from the inner ventricular wall to the outer cortex, are known to be the neural stem cells of the neocortex. Migrating neurons use these radial fibers to climb from the proliferative VZ in the inner part of the brain to the outer layers of the cortex, where differentiation processes continue. To establish the complex structures that constitute the adult cerebral cortex, proliferation, migration, and differentiation must be tightly controlled by various signaling events, including cytosolic Ca2+ signaling. During development, cells regularly exhibit spontaneous Ca2+ activity that stimulates downstream effectors, which can elicit these fundamental cell processes. Spontaneous Ca2+ activity during early neocortical development depends heavily on gap junctions and voltage dependent Ca2+ channels, whereas later in development neurotransmitters and synapses exert an influence. Here, we provide an overview of the literature on Ca2+ signaling and its impact on cell proliferation, migration, and differentiation in the neocortex. We point out important historical studies and review recent progress in determining the role of Ca2+ signaling in neocortical development. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 360-368, 2015

Inflammation-induced release of prostaglandin E2 (PGE2) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2 elicits a gap junction-dependent release of PGE2. This alters neural network activity in the preBötzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration. We used mice lacking eicosanoid prostanoid 3 receptors (EP3R), breathing brainstem organotypic slices and optogenetic inhibition of EP3R+/+ cells to demonstrate that the EP3R is important for the ventilatory response to hypercapnia. Our study identifies a novel pathway linking the inflammatory and respiratory systems, with implications for inspiration and sighs throughout life, and the ability to autoresuscitate when breathing fails. DOI: http://dx.doi.org/10.7554/eLife.14170.001, eLife digest Humans and other mammals breathe air to absorb oxygen into the body and to remove carbon dioxide. We know that in a part of the brain called the brainstem, several regions work together to create breaths, but it is not clear precisely how this works. These regions adjust our breathing to the demands placed on the body by different activities, such as sleeping or exercising. Sometimes, especially in newborn babies, the brainstem’s monitoring of oxygen and carbon dioxide does not work properly, which can lead to abnormal breathing and possibly death. In the brain, cells called neurons form networks that can rapidly transfer information via electrical signals. Here, Forsberg et al. investigated the neural networks in the brainstem that generate and control breathing in mice. They used slices of mouse brainstem that had been kept alive in a dish in the laboratory. The slice contained an arrangement of neurons and supporting cells that allowed it to continue to produce patterns of electrical activity that are associated with breathing. Over a three-week period, Forsberg et al. monitored the activity of the cells and calculated how they were connected to each other. The experiments show that the neurons responsible for breathing were organized in a “small-world” network, in which the neurons are connected to each other directly or via small numbers of other neurons. Further experiments tested how various factors affect the behavior of the network. For example, carbon dioxide triggered the release of a small molecule called prostaglandin E2 from cells. This molecule is known to play a role in inflammation and fever. However, in the carbon dioxide sensing region of the brainstem it acted as a signaling molecule that increased activity. Therefore, inflammation could interfere with the body’s normal response to carbon dioxide and lead to potentially life-threatening breathing problems. Furthermore, prostaglandin E2 induced deeper breaths known as sighs, which may be vital for newborn babies to be able to take their first deep breaths of life. Future challenges include understanding how the brainstem neural networks generate breathing and translate this knowledge to improve the treatment of breathing difficulties in babies. DOI: http://dx.doi.org/10.7554/eLife.14170.002

Coherent network activity among assemblies of interconnected cells is essential for diverse functions in the adult brain. However, cellular networks before formations of chemical synapses are poorly understood. Here, embryonic stem cell-derived neural progenitors were found to form networks exhibiting synchronous calcium ion (Ca(2+)) activity that stimulated cell proliferation. Immature neural cells established circuits that propagated electrical signals between neighboring cells, thereby activating voltage-gated Ca(2+) channels that triggered Ca(2+) oscillations. These network circuits were dependent on gap junctions, because blocking prevented electrotonic transmission both in vitro and in vivo. Inhibiting connexin 43 gap junctions abolished network activity, suppressed proliferation, and affected embryonic cortical layer formation. Cross-correlation analysis revealed highly correlated Ca(2+) activities in small-world networks that followed a scale-free topology. Graph theory predicts that such network designs are effective for biological systems. Taken together, these results demonstrate that immature cells in the developing brain organize in small-world networks that critically regulate neural progenitor proliferation.

Synchronized network activity among groups of interconnected cells is essential for diverse functions in the brain. However, most studies have been made on cellular networks in the mature brain when chemical synapses have been formed. Much less is known about the situation earlier in development. When studying neural progenitors derived from embryonic stem cells and neural progenitors from mice embryos, we found networks of gap junction coupled cells with vivid spontaneous non-random calcium (Ca(2+)) activity driven by electrical depolarization that stimulated cell growth. Network activity was revealed by single-cell live Ca(2+) imaging and further analyzed for correlations and network topology. The analysis revealed the networks to have small-world characteristics with scale-free properties. Taken together, these results demonstrate that immature cells in the developing brain organize in small-world networks that critically regulate neural progenitor proliferation.