Research reportThe role of cell death during neocortical neurogenesis and synaptogenesis: implications from a computational model for the rat and mouse
Introduction
The neocortex is thought to be the primary region for human thought, language, and behavior, and is the dominant structure of the mammalian brain [46]. During mammalian evolution, the neocortex has become an increasingly complex brain structure composed of at least six layers with 10 to 20 functional subdivisions, acting as representation maps of motor and sensory information. The basic function of the neocortex is the analysis and representation of the relationship between the components of sensory and motor patterns, which in turn support functions such as perception, motor programming, memory, language processing, and reasoning [30]. The latter functions in particular have become increasingly refined during primate evolution and are thought to be the hallmark of human intelligence. Understanding the cellular mechanisms of neocortical development is necessary in order for us to understand the evolution of the structure and how perturbations during development may cause long-term neocortical related deficits.
A systems level approach, incorporating molecular, cellular, organ, and behavioral analyses, in neurodevelopmental research will greatly enhance our understanding of mechanisms of normal neurodevelopmental processes and perturbations that may lead to neurodevelopmental disorders [39]. Under this premise, we have built a general mathematical model at the cellular level for normal neocortical development that simulates acquisition of adult neuronal cell number through neurogenesis [29]. To strengthen our current computational model for neocortical development, we extend the model to include programmed cell death during the period of neocortical synaptogenesis, postnatal day 0 to postnatal day 14 (P0–P14) in the rodent (roughly the 3rd trimester equivalent in humans).
Programmed cell death (PCD), or apoptosis, is an integral part of the development of the central nervous system and it has been estimated up to half of the original cell population is eliminated as a result of apoptosis [45], [53], [56]. Apoptosis of young neurons is thought to optimize synaptic connections by removing unnecessary neurons, often referred to as the nerve growth factor theory [26]. This theory postulates during the critical synaptogenesis period, competition of neurons for their targets determines the amount of neurotrophic factors received by the developing neurons. The messengers in this system are neurotrophic factors released from the postsynaptic target that regulate the release of cytochrome c and caspase activation [53]. The programmed cell death period has been characterized in the rat, cat, mouse, and hamster neocortex [56]. This process has also been reproduced in numerous primary in vitro culture systems through growth factor deprivation in young neurons [17], [18].
Recent research has implicated cell death may play a larger role in the earlier proliferative stages of neurodevelopment than previously thought [15], [40], [45]. For example, mice deficient in key apoptotic regulators, Caspase 3 and Caspase 9, show severe overgrowth of the ventricular region by E10.5, suggesting cell death plays a major role even before neurogenesis in the mouse [41], [42]. Furthermore, (all throughout the file) Blaschke et al. [3], using a novel protocol for an in situ end labeling technique (ISEL+) to detect dying cells, found that on average 50% of the proliferating cells during neurogenesis (E12–E18) are dying at any one time. Using Casp3−/− mice, only 18% of the ISEL+ staining was explained through the Caspase 3 pathway [58]. Although this research suggests cell death may play an important role well before the classical synaptogenesis period from which the neurotrophic theory evolved, others have shown cell death plays a relatively minor role during neurogenesis [7], [33], [75]. There is a critical need for quantitative analyses estimating how much early cell death affects final neocortical neuronal numbers [15]. Here we quantitatively analyze this data through simulations with varying cell death rates in our neurogenesis model.
Section snippets
Materials and methods
As in our neocortical neurogenesis model, our extended mathematical model of neocortical synaptogenesis was developed using a generalized, stochastic model framework for developmental processes in which a cellular population of relatively immature, undifferentiated cells going through periods of proliferation, differentiation, and apoptosis to form the final cell population, tissue, or organ of interest [44]. Here we develop several new applications of our generalized model. We have developed a
Model for programmed cell death during synaptogenesis
The time-dependent cell death rates calculated using the four studies described above and illustrated in Fig. 2 were used to extend our neurogenesis model to include PCD during the synaptogenesis period, predicting adult neocortical neuronal number and comparing these values with independent stereologically determined neuronal counts in the adult neocortex of the mouse and rat (Fig. 3). The use of the Verney et al. [76] and Thomaidou et al. [75] dataset predicts a 21% and 30% (1.6 and 1.4×107
Discussion
We have developed a computational model for rat and mouse neocortical development that includes neurogenesis and programmed cell death during synaptogenesis. To validate our models we compare our results to independently derived stereologically determined cell number data in the mouse and rat neocortex.
Our synaptogenesis model is robust when compared with independent estimates of percentages of neurons lost during this period. Independent data on neuronal number reduction in the neocortex due
Acknowledgements
This research was funded by the Center for Child Environmental Health Risks Research through EPA grant R826886, NIEHS grant 1PO1ES09601, Center for Ecogenetics and Environmental Health NIEHS grant 5P30ESO7033-03, Center of Human Development and Disability, The Environmental Pathology Training grant (T32ES07032), and the Seattle Chapter of the ARCS Foundation.
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