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Published on: November 20, 2015
Gestational Valproate Exposure Induces Tissue-Specific Transcriptomic Changes in the Neonatal Brain and Choroid
Fiona Qiu1, Yifan Huang1, Katarzyna M Dziegielewska1
1Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia.
Insights
Gestational exposure to valproate significantly impacts fetal brain development, altering gene expression in the choroid plexus and cortex. This valproate exposure may contribute to neurodevelopmental deficits in offspring.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Valproate is an essential antiseizure medication for epilepsy.
- Prenatal valproate exposure is linked to increased risks of neurodevelopmental deficits in children.
- The specific molecular mechanisms underlying these deficits remain incompletely understood.
Purpose of the Study:
- To investigate the impact of gestational valproate exposure on the developing brain's transcriptome.
- To compare the effects of valproate on the brain cortex and choroid plexus in early postnatal development.
- To identify potential molecular targets contributing to valproate-induced neurotoxicity.
Main Methods:
- Utilized the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model.
- Administered valproate via diet to pregnant rats from pre-mating through gestation.
- Performed RNA sequencing on brain cortex and lateral choroid plexus tissues from postnatal day 5 pups.
- Conducted differential gene expression analysis between valproate-exposed and control groups.
Main Results:
- Gestational valproate exposure caused significant transcriptomic alterations, with 5694 genes affected in the choroid plexus versus 214 in the cortex.
- Dysregulated genes in the choroid plexus included ion channels, metal transporters (e.g., Slc4a family), and drug transporters.
- Genes related to central nervous system development, drug metabolism, and immune responses were altered in both tissues, with more pronounced effects in the choroid plexus.
Conclusions:
- Gestational valproate exposure has a more profound and distinct effect on the choroid plexus transcriptome than the cerebral cortex.
- These findings suggest that the choroid plexus may be a critical target in understanding valproate-induced developmental neurotoxicity.
- Identifying these transcriptomic changes could lead to novel therapeutic strategies for mitigating valproate's adverse effects.
Abstract:
Valproate is an antiseizure drug required by many epileptic patients to manage their symptoms. During pregnancy, its use has been shown to increase the risk of neurobehavioral deficits in the offspring. The present study used a rat model of absence epilepsy, Genetic Absence Epilepsy Rat from Strasbourg (GAERS), to investigate the effects of gestational valproate exposure on early postnatal brain cortex and lateral choroid plexus transcriptomes. Females were provided with either a control diet or a valproate-laced diet (20 g/kg) from 2 weeks prior to mating and throughout gestation. At parturition, all dams received a control diet. Pups at Postnatal Day 5 were used for RNA sequencing. Differential expression analyses were conducted between transcriptomes from valproate-exposed and control animals. In the choroid plexus, 5694 genes significantly altered their expression compared to 214 in the cortex, a difference of nearly 25 times. Dysregulation was identified in choroidal expression of ion channels and metal transporters including six members of the Slc4a family, Cacna1h and Kcne2. Several drug transporting ATP-binding cassette transporters and solute carriers were significantly upregulated and drug-metabolising enzymes downregulated. In the cortex, 11 genes associated with the development of the central nervous system were differentially expressed. Finally, in both tissues, foetal valproate exposure appeared to result in dysregulation of genes related to adaptive and innate immune responses. These results indicated that gestational exposure to valproate resulted in distinct and greater effects on the choroid plexus transcriptome compared to the cortex, potentially suggesting additional targets related to developmental valproate neurotoxicity.
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