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Altered expression of KCC2 in GABAergic interneuron contributes prenatal stress-induced epileptic spasms in infant
Hyunjung Baek1, Min-Hee Yi2, Sudip Pandit3
1Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea; Department of Pediatrics, Chungnam National University Hospital, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 282, Jung-gu, Daejeon, 301-721, Republic of Korea.
Insights
Prenatal stress impairs the development of the gamma-aminobutyric acid (GABA) system in offspring, increasing seizure susceptibility. This occurs due to reduced GABA expression and altered KCC2 transporter function, leading to abnormal brain development.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Neuropharmacology
Background:
- Prenatal stress is linked to neurological deficits in offspring.
- The impact of prenatal stress on developing GABAergic interneurons and infantile seizures remains unclear.
Purpose of the Study:
- To investigate how prenatal stress affects the maturation of the GABA inhibitory system.
- To understand the mechanisms underlying increased seizure susceptibility in offspring exposed to prenatal stress.
Main Methods:
- Utilized prenatal stress models in rodents using betamethasone or acute immobilization stress (AIS).
- Assessed seizure susceptibility to N-methyl-d-aspartate (NMDA) triggered spasms.
- Measured the expression of GABA and glutamate decarboxylase 67 (GAD67).
- Quantified the expression of the K(+)/Cl(-) co-transporter (KCC2) in the cortex.
- Examined GABA-induced membrane depolarization and KCC2 expression in cultured brain slices.
Main Results:
- Prenatal stress significantly increased seizure susceptibility in offspring.
- Reduced expression of GABA and GAD67-positive cells was observed in stressed groups.
- Marked decrease in cortical KCC2 expression and increased GABA-induced membrane depolarization were noted.
- GABA administration increased KCC2 expression in cultured cortical slices.
Conclusions:
- Prenatal stress, via betamethasone or AIS, disrupts GABAergic system maturation, leading to diminished GABA input.
- This disruption results in decreased KCC2 expression and a lowered seizure threshold.
- A delayed excitatory/inhibitory shift in the cortical neuronal circuit contributes to seizure susceptibility in prenatal stress models.
Abstract:
Long-term stress during pregnancy causes neurologic deficits to offspring with altered gamma-aminobutyric acid (GABA) system in the brain. However, it is not clear how prenatal stress affects the maturing GABAergic interneurons and the resulting abnormalities in infantile seizures. Here, we showed that prenatal stress alters the maturation of GABA inhibitory system using a seizure model induced by prenatal stress. Prenatal stress with betamethasone or acute immobilization stress (AIS) on gestational day 15 increased the seizure susceptibility to N-methyl-d-aspartate-triggered spasms on postnatal day 15. The expression of GABA was lower in the prenatally stressed group, which compromise the decrease of glutamate decarboxylase 67-immunopositive cells. Prenatal stress markedly decreased the expression of K(+)/Cl(-) co-transporter (KCC2) in the cortex. GABA induced membrane depolarization demonstrated prenatal stress models had significant higher membrane depolarization compared to control. GABA increased KCC2 expression in cultured cortex-containing slices. Taken together, our results showed that prenatal stress with betamethasone or AIS altered the maturation of GABAergic progenitors and resulted in the lack of GABA input, which in turn, decreased KCC2 expression and lowered seizure threshold. We conclude that delayed GABA excitatory/inhibitory shift would render the cortical neuronal circuit more susceptible to excitatory input in prenatal stress induced seizure.
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