Review articleSelective vulnerability in the developing central nervous system
Introduction
In the term human neonate, damage to the deep gray nuclei and parasagittal regions is observed using magnetic resonance imaging modalities such as diffusion tensor imaging, magnetic resonance spectroscopy, and structural magnetic resonance imaging in the setting of neonatal encephalopathy [1], [2], [3] (Fig 1A,B). Various insults to the preterm human brain, on the other hand, result in predominantly white matter injury that later is reflected in loss of gray matter as the brain matures [4], [5] (Fig 2A). Selective cellular vulnerability may explain how these exquisitely precise and developmental stage-specific, region-selective injuries result from similar physiologic insults. In the mature brain, selective vulnerability accounts for characteristic features of certain neurodegenerative disorders: nigrostriatal neuron loss in Parkinson's disease, spinal motor neuron loss in amyotrophic lateral sclerosis, cholinergic basal forebrain neuron loss in Alzheimer's disease, and hippocampal CA1 neuron loss after global hypoxic-ischemic injury. In the immature brain, injury can be easily confused with maturational changes in the cytoarchitecture of the neurons residing there, for example the CA1 region of Ammon's horn, the least mature part of the hippocampal complex at birth [6].
This review will examine selective cellular vulnerability in the developing brain, emphasizing differences from the mature nervous system. Selective cellular vulnerability in the developing brain can be defined anatomically by the differential vulnerability of developing neuronal circuits, regionally by the presence of unique cell types, and neurochemically by the expression of signaling receptors for glutamate, and biosynthetic enzymes critical to synaptogenesis. Observations of selective vulnerability often imply mechanism. However, specific molecular mechanisms of selective vulnerability in the immature brain must be considered within the context of normal cell and systems development, and developmental differences in cellular defenses.
Section snippets
The premature infant: periventricular white matter injury
Injury to the periventricular white matter is the characteristic pattern observed in premature infants. In the following sections, we review the evidence supporting the involvement of cells in the oligodendrocyte lineage, as well as subplate neurons, in the pathogenesis of periventricular white matter injury.
The term infant: injury to deep gray nuclei and perirolandic cortex
Term human infants demonstrate a predilection for injury to thalamus and basal ganglia after a variety of insults (Fig 1A,B). Here we review evidence for the involvement of selected thalamic and striatal neurons in damage to the deep gray nuclei after hypoxia-ischemia in the term infant.
Mechanisms of selective vulnerability in the developing brain
Major pathogenic mechanisms of neuronal death include oxidative stress, glutamate receptor-mediated calcium-dependent excitotoxicity, and programmed cell death. In the following section, we will review each of these mechanisms as they relate to the examples we have given of selective vulnerability in the developing brain.
Summary
We have chosen examples of selective cellular vulnerability within the developing white matter and deep gray nuclei that may contribute to the observed patterns of injury observed at different ages of human brain development after a variety of insults. These examples are certainly not the complete story as selective vulnerability of astrocytes [87] and neural stem cells [88] have recently been reported. Furthermore, in distinction to the individual cell types we have discussed, the maturation
Acknowledgements
The authors would like to thank Frances Northington, Ann Sheldon, Stephen Back, and Orit Glenn for providing images for the figures. We would also like to thank Steve Miller and Shannon Hamrick for critical reading of the manuscript and Kei Kaneshiro for assistance with manuscript preparation.
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