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Preterm Birth Alters the Maturation of the GABAergic System in the Human Prefrontal Cortex
Helene Lacaille1, Claire-Marie Vacher1, Anna A Penn1
1Department of Pediatrics, Columbia University, NewYork-Presbyterian Morgan Stanley Children's Hospital, New York, NY, United States.
Insights
This study reveals sex-specific differences in brain development in infants. Premature birth significantly impacts the GABAergic system in male preterm infants, suggesting astrocyte involvement in brain injury.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Frontal lobe development involves GABAergic and glutamatergic systems, crucial for neurodevelopment.
- Alterations in these systems are linked to neurodevelopmental disorders in preterm or low birth weight infants.
- Cellular changes underlying these disorders remain largely unidentified.
Purpose of the Study:
- To investigate molecular development of the GABAergic system in the dorsolateral prefrontal cortex.
- To assess the impact of premature birth on GABAergic system maturation.
- To identify cellular mechanisms contributing to preterm brain injury.
Main Methods:
- Analysis of post-mortem human brain samples from term infants (0-8 months).
- Measurement of gene expression for 47 GABAergic genes to calculate a maturation index.
- Comparison of GABAergic system maturation between term and very preterm infants at 1 month corrected age.
Main Results:
- GABAergic system maturation index showed significant sex differences in term infants.
- Male preterm infants exhibited a significantly lower GABAergic system maturation index (-50%).
- Alterations were prominent in genes related to astrocytic GABAergic function in preterm infants.
Conclusions:
- GABAergic system development is sex-specific and dynamically altered by premature birth.
- Astrocytic GABAergic developmental changes represent a novel cellular mechanism in preterm brain injury.
- Findings provide insights into neurodevelopmental disorders associated with preterm birth.
Abstract:
Developmental changes in GABAergic and glutamatergic systems during frontal lobe development have been hypothesized to play a key role in neurodevelopmental disorders seen in children born very preterm or at/with low birth weight, but the associated cellular changes have not yet been identified. Here we studied the molecular development of the GABAergic system specifically in the dorsolateral prefrontal cortex, a region that has been implicated in neurodevelopmental and psychiatric disorders. The maturation state of the GABAergic system in this region was assessed in human post-mortem brain samples, from term infants ranging in age from 0 to 8 months (n = 17 male, 9 female). Gene expression was measured for 47 GABAergic genes and used to calculate a maturation index. This maturation index was significantly more dynamic in male than female infants. To evaluate the impact of premature birth on the GABAergic system development, samples from 1-month-old term (n = 9 male, 4 female) and 1-month corrected-age very preterm (n = 8 male, 6 female) infants, were compared using the same gene list and methodology. The maturation index for the GABAergic system was significantly lower (-50%, p < 0.05) in male preterm infants, with major alterations in genes linked to GABAergic function in astrocytes, suggesting astrocytic GABAergic developmental changes as a new cellular mechanism underlying preterm brain injury.
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