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GABAA receptor expression and white matter disruption in intrauterine growth restricted piglets
Viskasari P Kalanjati1, Julie A Wixey2, Stephanie M Miller2
1The University of Queensland, UQ Centre for Clinical Research, Perinatal Research Centre, Royal Brisbane and Women's Hospital, Brisbane, Queensland, 4029, Australia; Faculty of Medicine, Airlangga University, Surabaya, Indonesia.
Insights
Intrauterine growth restriction (IUGR) alters GABAergic system development in piglets, affecting brain white matter and neuronal structure. This may explain cognitive deficits in IUGR infants, highlighting targets for future treatments.
Area of Science:
- Neuroscience
- Developmental Biology
- Perinatal Medicine
Background:
- Intrauterine growth restriction (IUGR) is a significant cause of perinatal complications, often leading to white matter and neuronal injury in neonates.
- GABAA (γ-aminobutyric acid type A) receptors are implicated in oligodendrocyte development and myelination, crucial processes potentially disrupted in IUGR.
- The specific impact of IUGR on the GABAergic system and neuronal cytoskeleton development remains largely uncharacterized.
Purpose of the Study:
- To investigate alterations in GABAA receptor α1 and α3 subunit expression and distribution in the IUGR piglet brain.
- To examine the effects of IUGR on neuronal and myelination patterns during critical developmental stages.
- To correlate observed neurodevelopmental changes with potential cognitive impairments in IUGR.
Main Methods:
- Analysis of GABAA receptor α1 and α3 subunit protein expression in parietal cortex and hippocampus of IUGR piglets at multiple ages (100d, 104d, P0, P7).
- Immunohistochemical examination of neuronal somatodendrites using MAP2.
- Assessment of myelination patterns via myelin basic protein (MBP) immunolabelling.
Main Results:
- Significant changes in GABAA receptor subunit expression were observed in P7 IUGR piglets, with higher α3 than α1 expression in the hippocampus.
- A reduced α1/α3 ratio was noted in the parietal cortex of P7 IUGR piglets compared to controls.
- IUGR piglets exhibited reduced and disrupted neuronal somatodendrites (MAP2) and axonal fiber loss (MBP) from late gestation through the early postnatal period.
Conclusions:
- IUGR significantly impacts the developmental maturation of the GABAergic system and neuronal architecture in the developing brain.
- Altered GABAA receptor subunit expression patterns in IUGR may contribute to impaired myelination and white matter injury.
- These findings suggest that GABAergic system dysregulation is a key mechanism underlying neurodevelopmental deficits in IUGR, offering potential therapeutic targets.
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. GABAA (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 GABAA receptor α1 and α3 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 GABAA receptor α1 and α3 protein expression levels were observed in the IUGR piglet brain of P7 IUGR piglets with significantly greater α3 expression compared to α1 expression in the hippocampus while there was virtually no difference between the two subunits in the parietal cortex. However a significantly lower α1/α3 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 GABAA 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.
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