Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid

摘要

Highlights ? Prenatal VPA treatment caused an untimely enhancement of embryonic neurogenesis ? Prenatal VPA treatment has the long-term effect of impairing adult neurogenesis ? Reduced level of adult neurogenesis is associated with cognitive functional impairments ? Voluntary running can ameliorate the persistent detrimental effects caused by VPA Summary Prenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running. Graphical Abstract Figure options Download full-size image Download as PowerPoint slide prs.rt("abs_end"); Introduction Epilepsy is one of the most common neurological disorders in the world and is characterized by uncontrollable seizures ( Chang and Lowenstein, 2003 ). Epilepsy can affect anyone, at any age, and there are an estimated 50?million afflicted people worldwide ( Meinardi et?al., 2001 , Ngugi et?al., 2010 and Joint Epilepsy Council, 2011 ). The incidence of epilepsy is estimated to be higher than 0.5 cases per 1,000 of population per year ( Sander, 2003 ). Around 30% of sufferers are women of childbearing age ( Joint Epilepsy Council, 2011 ). During pregnancy, epileptic patients must balance the maternal and fetal risks associated with seizures against the potential teratogenicity of antiepileptic drugs (AEDs) ( Battino and Tomson, 2007 ). Although it was recently reported that several commonly used AEDs could produce?postnatal impairment of cognitive function if taken?during pregnancy ( Meador et?al., 2009 , Meador et?al., 2011 , Meador et?al., 2012 and Meador et?al., 2013 ), the precise pathology underlying such impairment remains unknown, and effective treatments for affected children of epileptic mothers who took AEDs during their pregnancy are therefore currently unavailable. Valproic acid (VPA [2-propylpentanoic acid]) is an established drug in the long-term treatment of epilepsy ( Blaheta and Cinatl, 2002 ). Several studies have revealed that VPA can directly inhibit histone deacetylase (HDAC) activity and cause hyperacetylation of histones, thereby activating gene transcription ( G?ttlicher et?al., 2001 and Phiel et?al., 2001 ). VPA significantly impairs postnatal cognitive function ( Meador et?al., 2009 , Meador et?al., 2011 , Meador et?al., 2012 and Meador et?al., 2013 ) and can lead to severe developmental defects if taken in early gestational stages ( DiLiberti et?al., 1984 and Nau et?al., 1991 ). We have previously shown, in several culture systems, that VPA enhances neurogenesis and drives neural precursor cells (NPCs) into the neuronal lineage over the glial lineage by a process involving HDAC inhibition ( Hsieh et?al., 2004 , Abematsu et?al., 2010 and Juliandi et?al., 2012 ). Here, we show that comparable postnatal cognitive functional impairment after prenatal VPA exposure in mice is caused by the untimely enhancement of embryonic neurogenesis, which leads to depletion of the NPCs pool and consequently a decreased level of adult neurogenesis in the hippocampus. We further show that hippocampal neurons in the offspring of VPA-treated mice have an abnormal morphology and activity. Nevertheless, these impairments can be alleviated by voluntary running.