Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice

Sakai, Atsuhiko; Matsuda, Takao; Doi, Hiroyoshi; Nagaishi, Yukiko; Kato, Kiyoko; Nakashima, Kinichi

doi:10.1073/pnas.1716479115

Cited by 35 publications

(34 citation statements)

References 59 publications

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“…Several studies have demonstrated that fetal and early-life exposure to various chemical substances in mammals can induce adverse effects after maturation (Fox, Grandjean, de Groot, & Paule, 2012;Juliandi et al, 2015;Newbold, Padilla-Banks, Jefferson, & Heindel, 2008;Sakai et al, 2018). In addition, it has been reported that many environmental chemical substances, such as bisphenol A, may cause adverse effects (e.g., abnormal behavior, immune function disorder and decreased fertility) in mammals at low levels of exposure ( Vandenberg et al, 2012).…”

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confidence: 99%

Early‐life exposure to low levels of permethrin exerts impairments in learning and memory with the effects on neuronal and glial population in adult male mice

Saito

Hara

Tominaga

et al. 2019

J of Applied Toxicology

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Permethrin, a pyrethroid chemical, is widely used as a pesticide because of its rapid insecticidal activity. Although permethrin is considered to exert very low toxicity in mammals, the effects of early, low‐level, chronic exposure on the adult central nervous system are unclear. In this study, we investigated the effects of low‐level, chronic permethrin exposure in early life on the brain functions of adult mice, using environmentally relevant concentrations. We exposed mice to the acceptable daily intake level of permethrin (0.3 ppm) in drinking water during the prenatal and postnatal periods. We then examined the effects on the central nervous system in adult male offspring. In the permethrin group, we detected behavior that displayed incomplete adaptation to a novel environment, as well as an impairment in learning and memory. In addition, immunohistochemical analysis revealed an increase in doublecortin‐ (an immature neuron marker) positive cells in the hippocampal dentate gyrus in the permethrin exposure group compared with the control group. Additionally, in the permethrin exposure group there was a decrease in astrocyte number in the hilus of the dentate gyrus, and remaining astrocytes were often irregularly shaped. These results suggest that exposure to permethrin at low levels in early life affects the formation of the neural circuit base and behavior after maturation. Therefore, in the central nervous system of male mice, low‐level, chronic permethrin exposure during the prenatal and postnatal periods has effects that were not expected based on the known effects of permethrin exposure in mature animals.

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confidence: 99%

Early‐life exposure to low levels of permethrin exerts impairments in learning and memory with the effects on neuronal and glial population in adult male mice

Saito

Hara

Tominaga

et al. 2019

J of Applied Toxicology

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“…While convulsions occurred at a low rate in both groups (c 2 = 0.75, p>0.3), continuous objectively derived home-cage measures were distinct: VPA-exposed mice displayed a blunted motor recovery and remained more distant from their counterparts ( Fig. 5F), suggesting enhanced seizure severity 51,52 .…”

Section: On Ethograms Of Chronic Vpa Exposurementioning

confidence: 95%

On the Digital Psychopharmacology of Valproic Acid in Mice

Bass

Tuo²,

Ton³

et al. 2020

Preprint

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ObjectiveAntiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anger, anxiety and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor developmental delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity.MethodsUsing instrumented home-cage monitoring, we assessed how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. By utilizing a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior.ResultsAt 500-600mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied chronically to breeder pairs of mice, VPA prolonged the latency to viable litters without affecting litter size. Two-week old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior.InterpretationThrough automated home-cage assessments of C57BL/6J mice, we capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating rigorous comprehensive assessments of neuropsychiatric tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring.

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“…It engages, among others, the Wnt1 signaling pathway, a robust ''caudalizing'' factor in the rostrocaudal patterning of CNS (Wiltse, 2005;Jang and Jeong, 2018). Prenatal VPA treatment altered the expression in neural stem/progenitor cells of genes associated with cell migration, including CXC motif chemokine receptor 4 (Cxcr4), leading to the ectopic localization of newborn neurons in the hilus of the hippocampus (Sakai et al, 2018). Importantly, of the 20 genes found to be downregulated in VPA-exposed marmoset neonates, Frizzled3 (FZD3) and PIK3CA have been implicated in the axon guidance signaling pathway required for the normal development of the anterior commissure and corpus callosum (Mimura et al, 2019).…”

Section: Transcriptional Effectsmentioning

confidence: 99%

Gestational Exposure to Sodium Valproate Disrupts Fasciculation of the Mesotelencephalic Dopaminergic Tract, With a Selective Reduction of Dopaminergic Output From the Ventral Tegmental Area

et al. 2020

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Gestational exposure to valproic acid (VPA) is known to cause behavioral deficits of sociability, matching similar alterations in human autism spectrum disorder (ASD). Available data are scarce on the neuromorphological changes in VPA-exposed animals. Here, we focused on alterations of the dopaminergic system, which is implicated in motivation and reward, with relevance to social cohesion. Whole brains from 7-day-old mice born to mothers given a single injection of VPA (400 mg/kg b.wt.) on E13.5 were immunostained against tyrosine hydroxylase (TH). They were scanned using the iDISCO method with a laser light-sheet microscope, and the reconstructed images were analyzed in 3D for quantitative morphometry. A marked reduction of mesotelencephalic (MT) axonal fascicles together with a widening of the MT tract were observed in VPA treated mice, while other major brain tracts appeared anatomically intact. We also found a reduction in the abundance of dopaminergic ventral tegmental (VTA) neurons, accompanied by diminished tissue level of DA in ventrobasal telencephalic regions (including the nucleus accumbens (NAc), olfactory tubercle, BST, substantia innominata). Such a reduction of DA was not observed in the non-limbic caudateputamen. Conversely, the abundance of TH+ cells in the substantia nigra (SN) was increased, presumably due to a compensatory mechanism or to an altered distribution of TH+ neurons occupying the SN and the VTA. The findings suggest that defasciculation of the MT tract and neuronal loss in VTA, followed by diminished dopaminergic input to the ventrobasal telencephalon at a critical time point of embryonic development (E13-E14) may hinder the patterning of certain brain centers underlying decision making and sociability.

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Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice

Cited by 35 publications

References 59 publications

Early‐life exposure to low levels of permethrin exerts impairments in learning and memory with the effects on neuronal and glial population in adult male mice

Early‐life exposure to low levels of permethrin exerts impairments in learning and memory with the effects on neuronal and glial population in adult male mice

On the Digital Psychopharmacology of Valproic Acid in Mice

Gestational Exposure to Sodium Valproate Disrupts Fasciculation of the Mesotelencephalic Dopaminergic Tract, With a Selective Reduction of Dopaminergic Output From the Ventral Tegmental Area

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