Dysmaturation of Somatostatin Interneurons Following Umbilical Cord Occlusion in Preterm Fetal Sheep.

Maryam Ardalan,Henrik Hagberg,Joakim Ek,Carina Mallard,Pernilla Svedin,Veena G Supramaniam,Ana A Baburamani

doi:10.3389/fphys.2019.00563

Maryam Ardalan, Henrik Hagberg + Show 5 more

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https://doi.org/10.3389/fphys.2019.00563

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Abstract

IntroductionCerebral white matter injury is the most common neuropathology observed in preterm infants. However, there is increasing evidence that gray matter development also contributes to neurodevelopmental abnormalities. Fetal cerebral ischemia can lead to both neuronal and non-neuronal structural-functional abnormalities, but less is known about the specific effects on interneurons.ObjectiveIn this study we used a well-established animal model of fetal asphyxia in preterm fetal sheep to study neuropathological outcome. We used comprehensive stereological methods to investigate the total number of oligodendrocytes, neurons and somatostatin (STT) positive interneurons as well as 3D morphological analysis of STT cells 14 days following umbilical cord occlusion (UCO) in fetal sheep.Materials and MethodsInduction of asphyxia was performed by 25 min of complete UCO in five preterm fetal sheep (98–100 days gestational age). Seven, non-occluded twins served as controls. Quantification of the number of neurons (NeuN), STT interneurons and oligodendrocytes (Olig2, CNPase) was performed on fetal brain regions by applying optical fractionator method. A 3D morphological analysis of STT interneurons was performed using IMARIS software.ResultsThe number of Olig2, NeuN, and STT positive cells were reduced in IGWM, caudate and putamen in UCO animals compared to controls. There were also fewer STT interneurons in the ventral part of the hippocampus, the subiculum and the entorhinal cortex in UCO group, while other parts of cortex were virtually unaffected (p > 0.05). Morphologically, STT positive interneurons showed a markedly immature structure, with shorter dendritic length and fewer dendritic branches in cortex, caudate, putamen, and subiculum in the UCO group compared with control group (p < 0.05).ConclusionThe significant reduction in the total number of neurons and oligodendrocytes in several brain regions confirm previous studies showing susceptibility of both neuronal and non-neuronal cells following fetal asphyxia. However, in the cerebral cortex significant dysmaturation of STT positive neurons occurred in the absence of cell loss. This suggests an abnormal maturation pattern of GABAergic interneurons in the cerebral cortex, which might contribute to neurodevelopmental impairment in preterm infants and could implicate a novel target for neuroprotective therapies.

Highlights

Cerebral white matter injury is the most common neuropathology observed in preterm infants
Post-mortem studies in preterm infants born at 25–32 weeks gestation, demonstrate that in addition to oligodendrocyte loss and axonal disruption, the number of GABAergic interneurons is significantly decreased in brains with white matter lesions (Robinson et al, 2006)
The number of STT interneurons was counted in different brain regions in block B: cortex, intragyral white matter (IGWM), periventricular white matter (PVWM), caudate and putamen (Figure 2) and block C: entorhinal cortex (EC), subiculum, and dentate gyrus (DG) subregion of dorsal and ventral hippocampi (Figure 3)

Summary

Introduction

Cerebral white matter injury is the most common neuropathology observed in preterm infants. Neurodevelopmental disability in infants and children born preterm, so called encephalopathy of prematurity, is associated with impaired cerebral maturation, including white and gray matter volumes, cortical folding, and gyral complexity (Boardman et al, 2006; Volpe, 2009). With respect to neuropathology, sheep have similar proportions of gray and white matter as the human (Mallard et al, 2003; Koehler et al, 2018) In these studies, we used a well-established animal model in preterm fetal sheep where asphyxia is induced by transient umbilical cord occlusion (UCO) at midgestation, which is equivalent to 25–30 weeks gestation in the human with respect to brain development (Mallard et al, 1994)

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