Systemic prenatal insults disrupt telencephalon development: implications for potential interventions

Abstract

Infants born prematurely are prone to chronic neurologic deficits including cerebral palsy, epilepsy, cognitive delay, behavioral problems, and neurosensory impairments. In affected children, imaging and neuropathological findings demonstrate significant damage to white matter. The extent of cortical damage has been less obvious. Advances in the understanding of telencephalon development provide insights into how systemic intrauterine insults affect the developing white matter, subplate, and cortex, and lead to multiple neurologic impairments. In addition to white matter oligodendrocytes and axons, other elements at risk for perinatal brain injury include subplate neurons, GABAergic neurons migrating through white matter and subplate, and afferents of maturing neurotransmitter systems. Common insults including hypoxia-ischemia and infection often affect the developing brain differently than the mature brain, and insults precipitate a cascade of damage to multiple neural lineages. Insights from development can identify potential targets for therapies to repair the damaged neonatal brain before it has matured.

Figure 1

Schematic of human telencephalon development. At 4-7 weeks, the preplate (PP) forms in the intermediate zone (IZ) between the ventricular zone and the marginal zone. At about 15 weeks, the early cortical plate cells create a division between the subplate and the marginal zone by migrating out radially from the VZ/SVZ. Subplate neurons form functional circuits with cortical plate neurons, other subplate neurons, and thalamocortical afferents. Upper subplate neurons form a dense band, while the density of neurons in the lower subplate is less. GABAergic neurons initially migrate tangentially to reach the appropriate cortical region, and then migrate radially out to the cortical plate beginning at 11 to 20 weeks. At about 25 weeks, the subplate reaches its maximal thickness, GABA expression peaks, catecholamine afferents arrive in the subplate, and oligodendrocytes and axons populate the subplate and IZ. Some migrating GABAergic neurons reach the cortical plate. During this developmental period GABAergic receptors are excitatory. By term, the subplate has aleady begun to recede. Conversely, between 30 and 40 weeks the cortical plate increases 4-fold. GABAergic neurons continue to migrate to the cortex. Cortical synapses mature and remodel. This schemata illustrates the components of the subplate and developing white matter that are potentially affected by white matter lesions. References: , , and .

Figure 2

Immunohistochemistry of the subplate and developing white matter from a 27 weeks gestation fetus without pathological changes suggestive of white matter damage. Coronal sections were cut from the frontal white matter at the level of the head of the caudate, and immunolabeled. The photomontage of the hematoxylin staining demonstrates the significant width of the subplate relative to the cortical plate at this period of development. Most O4+ prooligodendrocytes and O1+ oligodendrocytes are found in the lower subplate, while more neurons are present in the upper subplate. GAD-67+ cells are present in both the subplate and developing white matter. At this age, calretinin+ cells are located primarily in the developing white matter. Neuropeptide Y+ neurons develop extensive processes in the upper subplate. GABA_Aα1+ cells are located in the upper subplate, while GABA_BR1 receptor+ cells are mostly restricted to the developing white matter. Phosphorylated neurofilament immunolabeling (SMI #312) demonstrates a dense, mostly tangential band of axons is present in the lower subplate at this age. Hematoxylin bar = 100 μm, other bars = 10 μm.