Synaptic Development and Neuronal Myelination Are Altered with Growth Restriction in Fetal Guinea Pigs

Abstract

This study examines aberrant synaptogenesis and myelination of neuronal connections as possible links to neurological sequelae in growth-restricted fetuses. Pregnant guinea pig sows were subjected to uterine blood flow restriction or sham surgeries at midgestation. The animals underwent necropsy at term with fetuses grouped according to body weight and brain-to-liver weight ratios as follows: appropriate for gestational age (n = 12); asymmetrically fetal growth restricted (aFGR; n = 8); symmetrically fetal growth restricted (sFGR; n = 8), and large for gestational age (n = 8). Fetal brains were perfusion fixed and paraffin embedded to determine immunoreactivity for synaptophysin and synaptopodin as markers of synaptic development and maturation, respectively, and for myelin basic protein as a marker for myelination, which was further assessed using Luxol fast blue staining. The most pertinent findings were that growth-restricted guinea pig fetuses exhibited reduced synaptogenesis and synaptic maturation as well as reduced myelination, which were primarily seen in subareas of the hippocampus and associated efferent tracts. These neurodevelopmental changes were more pronounced in the sFGR compared to the aFGR animals. Accordingly, altered hippocampal development involving synaptogenesis and myelination may represent a mechanism by which cognitive deficits manifest in human growth-restricted offspring in later life.

Early Environmental Enrichment Enhances Abnormal Brain Connectivity in a Rabbit Model of Intrauterine Growth Restriction

“…Both DSs and PNNs have been involved in the regulation of synaptic connectivity and plasticity [43][44][45][46]. Our results showing decreased DS levels in IUGR rabbits are in line with previously described studies on guinea pig and sheep model showing changes in DS density and morphology along with changes in synaptic receptors after acute and chronic intrauterine insults [16,[47][48][49]. On the contrary, although there is growing interest in the description of PNN alterations related to specific brain diseases such as Alzheimer disease, schizophrenia, and epilepsy [45,50], the pattern of alterations in the PNNs related to IUGR had not been previously evaluated.…”

Dietary Selenium or Zinc Supplementation Restores Brain Lipid Composition and Membrane Fluidity in Protein-Undernourished Rats

“…Although, there may be several neurodevelopmental changes, as observed by Piorkowska et al [2] , leading to cognitive deficits in the developing brain, it can be concluded from this study that a perturbed lipid composition induced by PU affects the membrane structure and fluidity, and may contribute to the cognitive deficits that were earlier reported [6,7] . However, Se or Zn supplementation reversed the alterations in lipid composition and membrane fluidity, and may thus be beneficial in restoring the lipid dyshomeostasis associated with PU.…”

“…However, Se or Zn supplementation reversed the alterations in lipid composition and membrane fluidity, and may thus be beneficial in restoring the lipid dyshomeostasis associated with PU. The changes observed by Piorkowska et al [2] may also occur in our model, which should be further investigated in future studies.…”

Programming the brain: Common outcomes and gaps in knowledge from animal studies of IUGR

“…Volume ↓ cerebrum, E60 [162] ↓cerebellum E60 [142,162] Myelination ↓cerebrum, cerebellum, CA1 hippocampus, dorsal fornix, dorsal fimbria, corpus callosum, periventricular white matter, parasagittal white matter [119,121,143,206] =/↓ spine, age dependent [119] = subcortical white matter, d65 [143] Delayed maturation of myelin [162] ↓cerebral cortex, striatum [108] Thinner sheaths, signs of degeneration [108] Damage + lesions in cerebrum [108] + lesions, gliosis, axonal degeneration [109] Oligodendrocytes ↑ numbers in cerebellum [162] ASTROGLIOSIS Cerebrum = E52 [119] ↑E60, E62 [119,162] = E65 [143] ↑cortex [108,109] Striatum ↑ [108] Cerebellum = [119] ↑ E60 [162] Hippocampus = E65 [143] [79] ↓11% [90] ↓17.3% [128,129] ↓10-18% [116,212] = [125] Forebrain ↓10-15% [79,85] ↓ [129] ↓13-16% [145,162] ↓19% [212] = [125] Cortex ↓31% [128] ↓20% [217] Striatum ↓12% [212] Hippocampus = …”