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A Rat Model of Mild Intrauterine Hypoperfusion with Microcoil Stenosis
Published on: January 7, 2018
Intrauterine Growth Restriction Alters the Postnatal Development of the Rat Cerebellum
Annie R A McDougall1, Vanny Wiradjaja, Aminath Azhan
1The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Insights
Intrauterine growth restriction (IUGR) causes antenatal brain injury. IUGR in rats led to disorganized Bergmann glia and altered gene expression, impacting cerebellar development.
Area of Science:
- Neuroscience
- Developmental Biology
- Obstetrics
Background:
- Intrauterine growth restriction (IUGR) is a significant cause of antenatal brain injury.
- Cerebellar development is crucial for motor function and cognitive processes.
- Understanding IUGR's impact on the cerebellum is vital for addressing developmental deficits.
Purpose of the Study:
- To characterize cerebellar structural and molecular deficits in an IUGR rat model.
- To investigate the cellular and molecular mechanisms underlying IUGR-induced cerebellar injury.
- To identify potential therapeutic targets for mitigating IUGR's neurodevelopmental consequences.
Main Methods:
- Established an IUGR rat model via bilateral uterine vessel ligation.
- Collected offspring at postnatal days 2, 7, and 35 for analysis.
- Assessed body weight, cerebellar histology (EGL width, glial organization), and gene/protein expression (Trop2, Astn1).
Main Results:
- IUGR offspring exhibited reduced body weight and disorganized Bergmann glia.
- A significant decrease in Bergmann glial fiber density was observed by P35.
- Trophoblast antigen-2 (Trop2) mRNA and protein were reduced, while astrotactin 1 (Astn1) mRNA was increased in IUGR cerebellums at P7.
Conclusions:
- IUGR disrupts cerebellar development, affecting Bergmann glia and key developmental genes.
- Damage to the Bergmann glial migratory scaffold and altered gene expression (Trop2, Astn1) contribute to IUGR-related cerebellar deficits.
- These findings highlight potential mechanisms for IUGR-induced brain injury and suggest avenues for intervention.
Abstract:
Intrauterine growth restriction (IUGR) is a major cause of antenatal brain injury. We aimed to characterize cerebellar deficits following IUGR and to investigate the potential underlying cellular and molecular mechanisms. At embryonic day 18, pregnant rats underwent either sham surgery (controls; n = 23) or bilateral uterine vessel ligation to restrict blood flow to fetuses (IUGR; n = 20). Offspring were collected at postnatal day 2 (P2), P7, and P35. Body weights were reduced at P2, P7, and P35 in IUGR offspring (p < 0.05) compared with controls. At P7, the width of the external granule layer (EGL) was 30% greater in IUGR than control rats (p < 0.05); there was no difference in the width of the proliferative zone or in the density of Ki67-positive cells in the EGL. Bergmann glia were disorganized at P7 and P35 in IUGR pups, and by P35, there was a 10% decrease in Bergmann glial fiber density (p < 0.05) compared with controls. At P7, trophoblast antigen-2 (Trop2) mRNA and protein levels in the cerebellum were decreased by 88 and 40%, respectively, and astrotactin 1 mRNA levels were increased by 20% in the IUGR rats (p < 0.05) compared with controls; there was no difference in ASTN1 protein. The expressions of other factors known to regulate cerebellar development (astrotactin 2, brain-derived neurotrophic factor, erb-b2 receptor tyrosine kinase 4, neuregulin 1, sonic hedgehog and somatostatin) were not different between IUGR and control rats at P7 or P35. These data suggest that damage to the migratory scaffold (Bergmann glial fibers) and alterations in the genes that influence migration (Trop2 and Astn1) may underlie the deficits in postnatal cerebellar development following IUGR.
