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

摘要

class="head no_bottom_margin" id="sec1title">IntroductionEpilepsy is one of the most common neurological disorders in the world and is characterized by uncontrollable seizures (). Epilepsy can affect anyone, at any age, and there are an estimated 50 million afflicted people worldwide (, , ). The incidence of epilepsy is estimated to be higher than 0.5 cases per 1,000 of population per year (). Around 30% of sufferers are women of childbearing age (). During pregnancy, epileptic patients must balance the maternal and fetal risks associated with seizures against the potential teratogenicity of antiepileptic drugs (AEDs) (). Although it was recently reported that several commonly used AEDs could produce postnatal impairment of cognitive function if taken during pregnancy (, , , ), 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 (). Several studies have revealed that VPA can directly inhibit histone deacetylase (HDAC) activity and cause hyperacetylation of histones, thereby activating gene transcription (, ). VPA significantly impairs postnatal cognitive function (, href="#bib30" rid="bib30" class=" bibr popnode">Meador et al., 2011, href="#bib31" rid="bib31" class=" bibr popnode">Meador et al., 2012, href="#bib32" rid="bib32" class=" bibr popnode">Meador et al., 2013) and can lead to severe developmental defects if taken in early gestational stages (href="#bib9" rid="bib9" class=" bibr popnode">DiLiberti et al., 1984, href="#bib36" rid="bib36" class=" bibr popnode">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 (href="#bib16" rid="bib16" class=" bibr popnode">Hsieh et al., 2004, href="#bib1" rid="bib1" class=" bibr popnode">Abematsu et al., 2010, href="#bib20" rid="bib20" class=" bibr popnode">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.