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Altered Development of Prefrontal GABAergic Functions and Anxiety-like Behavior in Adolescent Offspring Induced by
Arbthip Suwaluk1, Nuanchan Chutabhakdikul1
1Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73130, Thailand.
Insights
Prenatal stress in rats impairs prefrontal cortex GABAergic system development, leading to increased anxiety-like behaviors in adolescent offspring. This disruption affects key proteins crucial for brain maturation and function.
Area of Science:
- Neuroscience
- Developmental Psychology
- Molecular Biology
Background:
- Maternal stress during gestation can negatively impact fetal brain development.
- Prenatal stress (PS) is linked to cognitive deficits, particularly anxiety, in offspring.
- The prefrontal cortex (PFC) is a brain region with prolonged maturation, susceptible to early-life stress.
Purpose of the Study:
- To investigate the long-lasting effects of prenatal stress on the GABAergic system in the adolescent rat prefrontal cortex.
- To determine how prenatal stress influences GABAergic signaling proteins and neuronal plasticity markers in offspring.
Main Methods:
- Pregnant rats were exposed to restraint stress during the final week of gestation.
- Adolescent male offspring were assessed for anxiety-like behavior using the elevated plus maze (EPM) test.
- Levels of key GABAergic proteins (KCC2, NKCC1, GABAAR α1/α5 subunits, parvalbumin) and pCREB were measured in PFC tissue.
Main Results:
- Prenatal stress offspring exhibited heightened anxiety-like behavior.
- Significant reductions in KCC2, GABAAR α1 subunit, parvalbumin, and pCREB levels were observed in the PFC of stressed offspring.
- These molecular changes indicate a disruption in GABAergic signaling and neuronal plasticity.
Conclusions:
- Prenatal stress disrupts the maturation of the prefrontal cortex GABAergic system.
- Reduced GABAergic function and plasticity markers in adolescence are associated with increased anxiety.
- These findings suggest a potential neurobiological basis for anxiety disorders developing from early-life stress.
Abstract:
Maternal stress can afflict fetal brain development, putting the offspring at risk of cognitive deficits, including anxiety. The prefrontal cortex (PFC), a protracted maturing region, is notably affected by prenatal stress (PS). However, it remains unclear how PS interferes with the maturation of the GABAergic system, considering its functional adjustment in the PFC during adolescence. The present study thus investigated the long-lasting consequences of PS on the prefrontal GABAergic functions of adolescent offspring. Pregnant Sprague-Dawley rats were divided into controls and the PS group, which underwent restraint stress during the last week of gestation. Male pups from postnatal days (PND) 40-42 were submitted to the elevated plus maze (EPM) test. Proteins essentially involved in GABAergic signaling were then examined in PFC tissues, including the K+-Cl- cotransporter (KCC2), Na+-K+-Cl- cotransporter (NKCC1), α1 and α5 subunits of GABA type A receptors (GABAA receptors), and parvalbumin (PV), along with cAMP response element-binding protein phosphorylation (pCREB), which reacts in the plasticity regulation of PV-positive interneurons. The results revealed that the higher anxiety-like behavior of PS adolescent rats concurred with the significant decreases of the KCC2 and α1 subunits, with PV- and pCREB-lowered levels. The findings suggested that PS disrupts the continuance of PFC maturity by reducing the essential elements of GABAergic functions. These changes likely underlie the anxiety emerging in adolescence, possibly progressing to mental disorders.
