Abstract
Epilepsy is a prominent sign of neurological dysfunction in children with various fetal and maternal deficiencies. However, the detailed mechanism and influences underlying epileptic disorders are still unrevealed. The hippocampal neurons are vulnerable to epilepsy-induced pathologic changes and often manifests as neuronal death. The present study was designed to investigate the effect of maternal epileptic seizure on apoptotic neuronal death, modulation of GABAB1 receptor (R), and protein kinase A-α (PKA) in prenatal rat hippocampal neurons at gestational days (GD) 17.5. Seizure was induced in pregnant rat using intraperitoneal injection of pentylenetetrazol (PTZ) (40 mg/kg for 15 days). To confirm the seizure electroencephalography (EEG) data was obtained by the Laxtha EEG-monitoring device in the EEG recording room and EEG were monitored 5 min and 15 min after PTZ injection. The RT-PCR and Western blot results showed significant increased expression of cytochrome-c and caspases-3, while decreased levels of GABAB1R, and PKA protein expression upon ethanol, PTZ and ethanol plus PTZ exposure in primary neuronal cells cultured from PTZ-induced seizure model as compare to non-PTZ treated maternal group. Apoptotic neurodegeneration was further confirmed with Fluoro-Jade B and propidium iodide staining, where neurons were scattered and shrunken, with markedly condensed nuclei in PTZ treated group compared with control. This study for the first time indicate that PTZ-induced seizures triggered activation of caspases-3 to induce widespread apoptotic neuronal death and decreased GABAB1R expression in hippocampal neurons, providing a possible mechanistic link between maternal epilepsy induced neurodegeneration alteration of GABAB1R and PKA expression level during prenatal brain development. This revealed new aspects of PTZ and ethanol's modulation on GABAB1R, learning and memory. Further, explain the possibility that children delivered by epileptic mothers may have higher risk of developmental disturbances and malformations.
Highlights
It is well established that the development of an organism is determined by genetic, and postnatal environment effects, and by prenatal effects e.g. during gestation
Explain the possibility that children delivered by epileptic mothers may have higher risk of developmental disturbances and malformations
Our results revealed that PTZ-induced seizure cause apoptotic neurodegeneration, and decreased GABAB1R expression which further leads to intracellular changes at protein kinase A-α (PKA) expression level
Summary
It is well established that the development of an organism is determined by genetic, and postnatal environment effects, and by prenatal effects e.g. during gestation. Modifications of various neurotransmitter systems and neuronal excitability can be induced at early stages of development by behavioural procedures and by prenatal exposure of various substances [1,2,3]. Molecular Brain 2009, 2:20 http://www.molecularbrain.com/content/2/1/20 it is well established that children delivered by epileptic mothers may have a higher risk of developmental disturbances and malformations [4]. Epileptic convulsions have significant influences on brain structure and are able to induce neuron death. The detailed molecular mechanisms are still under investigation, present physiological and genetic analysis reveal that epilepsy is closely related with the various ion channels including voltage-gated channels (Na+, K+, Ca2+, Cl-) and ligandgated channels (nicotinic acetylcholine and GABAA receptors)
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