Several types of brain disorders enhance the death of immature neurons (i.e., postmitotic neurons, but before complete maturation) during brain development that could lead to decline in cognitive abilities. Disturbances in regulating developmental neuronal death not only change cell composition and connectivity within local neuronal networks, but also alter global brain activity and, thus, cognition. 6, 7, 8, 9 The process of neuronal overproduction and elimination is necessary to optimize brain connectivity. 1, 2, 3, 4, 5 A high rate of neuronal death also occurs in the regions of adult neurogenesis. What mechanisms account for higher vulnerability of immature neurons to stress factors?ĭuring brain development, an excessive number of neurons is generated and, depending on the region and neuronal type, a varying number of neurons die before they mature. Importantly, we mainly focus on in vivo data to describe neuronal survival specifically in the brain, without extrapolating data obtained in the PNS or spinal cord, and thus emphasize the influence of the complex brain environment on neuronal survival during development. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various types of immature neurons. Thus, in addition to some common neuronal pro-survival signaling, different types of neurons possess a variety of 'neuron type-specific' pro-survival constituents that might help them to adapt for survival in a certain brain region. Furthermore, pro-survival factors and intracellular responses depend on the type of neuron and region of the brain.
To accommodate this signaling, immature neurons in the brain express a number of transmembrane factors as well as intracellular signaling molecules that will regulate the cell survival/death decision, and many of these factors cease being expressed upon neuronal maturation. External signals from brain microenvironment together with intrinsic signaling pathways determine whether a particular neuron will die.
Removal of substantial numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage.
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