GABA_A receptor expression and white matter disruption in intrauterine growth restricted piglets

Abstract

Intrauterine growth restriction (IUGR) is one of the most common causes of perinatal mortality and morbidity. White matter and neuronal injury are major pathophysiological features of the IUGR neonatal brain. GABA (γ-aminobutyric acid type A) receptors have been shown to play a role in oligodendrocyte differentiation and proliferation in the neonatal brain and may be a key factor in white matter injury and myelination in IUGR neonates. Whether there are impairments to the GABAergic system and neuronal cytoskeleton in IUGR brain has yet to be elucidated. This study aims to examine GABA receptor α and α subunit protein expression and distribution in parietal cortex and hippocampus of the IUGR piglet at four different ages (term=115d - days gestational age), 100d, 104d, birth (postnatal day 0-P0) and P7 and to examine neuronal and myelination patterns. Significant alterations to GABA receptor α and α protein expression levels were observed in the IUGR piglet brain of P7 IUGR piglets with significantly greater α expression compared to α expression in the hippocampus while there was virtually no difference between the two subunits in the parietal cortex. However a significantly lower α/α ratio was evident in P7 IUGR cortex when compared with P7 NG cortex. Neuronal somatodendrites studied using MAP2 immunohistochemistry showed reduced and disrupted somatodendrites while MBP immunolabelling showed loss of axonal fibres from gestational day 104d through to P7. These findings provide insights into the effects of IUGR on the development of the GABA system, altered developmental maturation of GABA receptor subunit expression in the IUGR brain may influence myelination and may partly explain the cognitive disabilities observed in IUGR. Understanding the mechanisms behind grey and white matter injury in the IUGR infant is essential to identifying targets for treatments to improve long-term outcomes for IUGR infants.

Neuropathology in intrauterine growth restricted newborn piglets is associated with glial activation and proinflammatory status in the brain

“…1a). We have previously shown impaired neuronal morphology in the IUGR piglet brain [11]; however, it was not clear whether the neurons were degenerating and undergoing cell death. Therefore, in the current study, we also examined neuronal degeneration using FJC.…”

“…Litter-matched pairs were obtained from multiple sows ( n = 11). The IUGR piglet model is well-established and characterised by our group and others [11, 33]. This model is caused by placental insufficiency [33]; the most common cause of IUGR in the human population.…”

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

“…Alterations in dendritic arborization have been found in the GM in a number of experimental studies, many of which have already been referred to above [e.g., (103,138)]. Additionally, a model of intrauterine growth restriction in pig, initiated at 100 days of pregnancy and assessed 22 days later, showed a loss of MAP2 staining in the parietal cortex and hippocampus, which was interpreted as disrupted somatodendritic neurites (162). Intrauterine growth restriction is an important contributor to poor perinatal outcomes, particularity in preterm born infants [see (163)].…”

Therapeutic potential to reduce brain injury in growth restricted newborns

“…Preclinical IUGR piglet studies demonstrate that brain injury occurs late in gestation and continues postnatally (Kalanjati et al . ). The spontaneous/naturally occurring IUGR piglet shows neuronal and white matter injury from 104 days of gestation (term = 115 days) to postnatal day 7, with no significant white matter or neuronal injury detected at 100 days of gestation.…”