scholarly journals Pentylenetetrazole-induced seizures in developing rats prenatally exposed to valproic acid

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2709
Author(s):  
Angel A. Puig-Lagunes ◽  
Jorge Manzo ◽  
Luis Beltrán-Parrazal ◽  
Consuelo Morgado-Valle ◽  
Rebeca Toledo-Cárdenas ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Clonic Seizure ◽  
Autism Spectrum ◽  
Seizure Susceptibility ◽  
Prenatally Exposed ◽  
Seizure Severity ◽  
Pregnant Females ◽  
Rat Pups ◽  
Spectrum Disorders ◽  
And Control

Background Epidemiological evidence indicates epilepsy is more common in patients with autism spectrum disorders (ASD) (20–25%) than in the general population. The aim of this project was to analyze seizure susceptibility in developing rats prenatally exposed to valproic acid (VPA) as autism model. Methods Pregnant females were injected with VPA during the twelfth embryonic day. Seizures were induced in fourteen-days-old rat pups using two models of convulsions: pentylenetetrazole (PTZ) and lithium-pilocarpine (Li-Pilo). Results Two subgroups with different PTZ-induced seizure susceptibility in rats exposed to VPA were found: a high susceptibility (VPA+) (28/42, seizure severity 5) and a low susceptibility (VPA−) (14/42, seizure severity 2). The VPA+ subgroup exhibited an increased duration of the generalized tonic-clonic seizure (GTCS; 45 ± 2.7 min), a higher number of rats showed several GTCS (14/28) and developed status epilepticus (SE) after PTZ injection (19/27) compared with control animals (36.6 ± 1.9 min; 10/39; 15/39, respectively). No differences in seizure severity, latency or duration of SE induced by Li-Pilo were detected between VPA and control animals. Discussion Prenatal VPA modifies the susceptibility to PTZ-induced seizures in developing rats, which may be linked to an alteration in the GABAergic transmission. These findings contribute to a better understanding of the comorbidity between autism and epilepsy.

scholarly journals Downregulation of CD40L–CD40 attenuates seizure susceptibility and severity of seizures

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Esther Pototskiy ◽  
Katherine Vinokuroff ◽  
Andrew Ojeda ◽  
C. Kendall Major ◽  
Deepak Sharma ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Molecular Techniques ◽  
Seizure Susceptibility ◽  
Wild Type ◽  
Upward Trend ◽  
Seizure Severity ◽  
Cd40 Expression ◽  
Neuro Inflammation ◽  
And Control ◽  
Deficient Mice

AbstractUnregulated neuro-inflammation mediates seizures in temporal lobe epilepsy (TLE). Our aim was to determine the effect of CD40–CD40L activation in experimental seizures. CD40 deficient mice (CD40KO) and control mice (wild type, WT) received pentenyltetrazole (PTZ) or pilocarpine to evaluate seizures and status epilepticus (SE) respectively. In mice, anti-CD40L antibody was administered intranasally before PTZ. Brain samples from human TLE and post-seizure mice were processed to determine CD40–CD40L expression using histological and molecular techniques. CD40 expression was higher in hippocampus from human TLE and in cortical neurons and hippocampal neural terminals after experimental seizures. CD40–CD40L levels increased after seizures in the hippocampus and in the cortex. After SE, CD40L/CD40 levels increased in cortex and showed an upward trend in the hippocampus. CD40KO mice demonstrated reduction in seizure severity and in latency compared to WT mice. Anti-CD40L antibody limited seizure susceptibility and seizure severity. CD40L–CD40 interaction can serve as a target for an immuno-therapy for TLE.

scholarly journals DENTATE GYRUS MOLECULAR LAYER MICROGLIA CHANGES, IL1-β AND BEHAVIOR IN MOUSE VALPROIC ACID MODEL OF AUTISM SPECTRUM DISORDERS

2019 ◽  
Author(s):  
Alinne Lorrany Gomes Dos Santos ◽  
Ellen Rose Leandro Ponce de Leão ◽  
Larissa Victória Barra de Moura ◽  
Dilza Souza ◽  
Daniel Guerreiro Diniz ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Autism Spectrum Disorders ◽  
Dentate Gyrus ◽  
Molecular Layer ◽  
Autism Spectrum ◽  
Spectrum Disorders ◽  
And Behavior

scholarly journals No Association between the rs1799836 Polymorphism of the Monoamine Oxidase B Gene and the Risk of Autism Spectrum Disorders in the Kazakhstani Population

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Anastassiya V. Perfilyeva ◽  
Kira B. Bespalova ◽  
Liliya A. Skvortsova ◽  
Assel Surdeanu ◽  
Aleksandr A. Garshin ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Large Scale ◽  
Genetic Factors ◽  
Genetic Variant ◽  
Autism Spectrum ◽  
Healthy Siblings ◽  
Hardy Weinberg Equilibrium ◽  
Spectrum Disorders ◽  
And Control ◽  
Gender Specific

Autism spectrum disorders (ASDs) are heterogeneous diseases that are triggered by a number of environmental and genetic factors. The aim of the current study was to investigate an association of the rs1799836 genetic variant of the neurotransmitter-related gene MAOB with ASDs. In total, 262 patients diagnosed with ASDs and their 126 healthy siblings were included in the present study. All individuals represented a Kazakhstani population. The distributions of the rs1799836 genotype were in accordance with the Hardy-Weinberg equilibrium among both cases and controls. No statistically significant differences were found in the allelic distributions of this polymorphism between ASD and control subjects (A/G: for males OR=1.11, 95% 0.59-2.06, p=0.75; for females OR=1.14, 95% 0.70-1.86, p=0.76). However, the increased score in the overall CARS was significantly associated with the A allele of rs1799836 MAOB for females (OR=2.31, 95% 1.06-5.04, p=0.03). The obtained results suggest that the rs1799836 polymorphism of the MAOB gene may have little contribution to the development of ASDs but may be involved in pathways contributing to ASD symptom severity in females. Further large-scale investigations are required to uncover possible relationships between rs1799836 MAOB and ASD progression in a gender-specific manner and their possible application as a therapeutic target.

scholarly journals Bisphenol A Exposure in utero Disrupts Hypothalamic Gene Expression Particularly Genes Suspected in Autism Spectrum Disorders and Neuron and Hormone Signaling

2020 ◽  
Vol 21 (9) ◽  
pp. 3129
Author(s):  
Anne D. Henriksen ◽  
Alejandro Andrade ◽  
Erin P. Harris ◽  
Emilie F. Rissman ◽  
Jennifer T. Wolstenholme
Keyword(s):  
Gene Expression ◽  
Autism Spectrum Disorders ◽  
Bisphenol A ◽  
In Utero ◽  
Autism Spectrum ◽  
Differentially Expressed ◽  
Basal Nucleus ◽  
Spectrum Disorders ◽  
And Control ◽  
Upstream Regulators

Bisphenol A (BPA) is an endocrine-disrupting compound detected in the urine of more than 92% of humans, easily crosses the placental barrier, and has been shown to influence gene expression during fetal brain development. The purpose of this study was to investigate the effect of in utero BPA exposure on gene expression in the anterior hypothalamus, the basal nucleus of the stria terminalis (BNST), and hippocampus in C57BL/6 mice. Mice were exposed in utero to human-relevant doses of BPA, and then RNA sequencing was performed on male PND 28 tissue from whole hypothalamus (n = 3/group) that included the medial preoptic area (mPOA) and BNST to determine whether any genes were differentially expressed between BPA-exposed and control mice. A subset of genes was selected for further study using RT-qPCR on adult tissue from hippocampus to determine whether any differentially expressed genes (DEGs) persisted into adulthood. Two different RNA-Seq workflows indicated a total of 259 genes that were differentially expressed between BPA-exposed and control mice. Gene ontology analysis indicated that those DEGs were overrepresented in categories relating to mating, cell–cell signaling, behavior, neurodevelopment, neurogenesis, synapse formation, cognition, learning behaviors, hormone activity, and signaling receptor activity, among others. Ingenuity Pathway Analysis was used to interrogate novel gene networks and upstream regulators, indicating the top five upstream regulators as huntingtin, beta-estradiol, alpha-synuclein, Creb1, and estrogen receptor (ER)-alpha. In addition, 15 DE genes were identified that are suspected in autism spectrum disorders.

scholarly journals Prenatal Exposure to Valproic Acid Affects Microglia and Synaptic Ultrastructure in a Brain-Region-Specific Manner in Young-Adult Male Rats: Relevance to Autism Spectrum Disorders

2020 ◽  
Vol 21 (10) ◽  
pp. 3576 ◽  
Author(s):  
Magdalena Gąssowska-Dobrowolska ◽  
Magdalena Cieślik ◽  
Grzegorz Arkadiusz Czapski ◽  
Henryk Jęśko ◽  
Małgorzata Frontczak-Baniewicz ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Autism Spectrum Disorders ◽  
Young Adult ◽  
Prenatal Exposure ◽  
Adult Male ◽  
Brain Region ◽  
Autism Spectrum ◽  
Synaptic Proteins ◽  
Specific Manner ◽  
Spectrum Disorders

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions categorized as synaptopathies. Environmental risk factors contribute to ASD aetiology. In particular, prenatal exposure to the anti-epileptic drug valproic acid (VPA) may increase the risk of autism. In the present study, we investigated the effect of prenatal exposure to VPA on the synaptic morphology and expression of key synaptic proteins in the hippocampus and cerebral cortex of young-adult male offspring. To characterize the VPA-induced autism model, behavioural outcomes, microglia-related neuroinflammation, and oxidative stress were analysed. Our data showed that prenatal exposure to VPA impaired communication in neonatal rats, reduced their exploratory activity, and led to anxiety-like and repetitive behaviours in the young-adult animals. VPA-induced pathological alterations in the ultrastructures of synapses accompanied by deregulation of key pre- and postsynaptic structural and functional proteins. Moreover, VPA exposure altered the redox status and expression of proinflammatory genes in a brain region-specific manner. The disruption of synaptic structure and plasticity may be the primary insult responsible for autism-related behaviour in the offspring. The vulnerability of specific synaptic proteins to the epigenetic effects of VPA may highlight the potential mechanisms by which prenatal VPA exposure generates behavioural changes.

scholarly journals Micromolar Valproic Acid Doses Preserve Survival and Induce Molecular Alterations in Neurodevelopmental Genes in Two Strains of Zebrafish Larvae

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1364
Author(s):  
Andrea Messina ◽  
Alessandra Boiti ◽  
Valeria Anna Sovrano ◽  
Paola Sgadò
Keyword(s):  
Valproic Acid ◽  
Epidemiological Studies ◽  
Autism Spectrum ◽  
Embryo Survival ◽  
Molecular Alterations ◽  
Zebrafish Larvae ◽  
Embryonic Exposure ◽  
Anxiety Behavior ◽  
Spectrum Disorders ◽  
Shed Light

Autism spectrum disorders (ASDs) comprise a genetically heterogeneous group of conditions characterized by a multifaceted range of impairments and multifactorial etiology. Epidemiological studies have identified valproic acid (VPA), an anticonvulsant used to treat epilepsy, as an environmental factor for ASDs. Based on these observations, studies using embryonic exposure to VPA have been conducted in many vertebrate species to model ASD. The zebrafish is emerging as a popular model in biomedical research to study the molecular pathways involved in nervous system disorders. VPA exposure in zebrafish larvae has been shown to produce a plethora of effects on social, motor and anxiety behavior, and several genetic pathways altered by VPA have been described. However, the doses and regimen of administration reported in the literature are very heterogenous, creating contradictory results and posing serious limits to the interpretation of VPA action on neurodevelopment. To shed light on the toxic effect of VPA, we tested micromolar concentrations of VPA, using exposure for 24 and 48 h in two different zebrafish strains. Our results show that micromolar doses of VPA mildly affect embryo survival but are sufficient to induce molecular alterations in neurodevelopmental genes previously shown to be influenced by VPA, with substantial differences between strains.

scholarly journals Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid

2013 ◽  
Vol 16 (1) ◽  
pp. 91-103 ◽  
Author(s):  
Shunsuke Kataoka ◽  
Kazuhiro Takuma ◽  
Yuta Hara ◽  
Yuko Maeda ◽  
Yukio Ago ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Social Interaction ◽  
Prenatal Exposure ◽  
Apoptotic Cell ◽  
Autism Spectrum ◽  
Prenatally Exposed ◽  
Histone Deacetylase Inhibition ◽  
Histone Hyperacetylation ◽  
The Social ◽  
Cortical Pathology

Abstract Maternal use of valproic acid (VPA) during pregnancy has been implicated in the aetiology of autism spectrum disorders in children, and rodents prenatally exposed to VPA showed behavioural alterations similar to those observed in humans with autism. However, the exact mechanism for VPA-induced behavioural alterations is not known. To study this point, we examined the effects of prenatal exposure to VPA and valpromide, a VPA analog lacking histone deacetylase inhibition activity, on behaviours, cortical pathology and histone acetylation levels in mice. Mice exposed to VPA at embryonic day 12.5 (E12.5), but not at E9 and E14.5, displayed social interaction deficits, anxiety-like behaviour and memory deficits at age 4–8 wk. In contrast to male mice, the social interaction deficits (a decrease in sniffing behaviour) were not observed in female mice at age 8 wk. The exposure to VPA at E12.5 decreased the number of Nissl-positive cells in the middle and lower layers of the prefrontal cortex and in the lower layers of the somatosensory cortex at age 8 wk. Furthermore, VPA exposure caused a transient increase in acetylated histone levels in the embryonic brain, followed by an increase in apoptotic cell death in the neocortex and a decrease in cell proliferation in the ganglionic eminence. In contrast, prenatal exposure to valpromide at E12.5 did not affect the behavioural, biochemical and histological parameters. Furthermore, these findings suggest that VPA-induced histone hyperacetylation plays a key role in cortical pathology and abnormal autism-like behaviours in mice.

scholarly journals DENTATE GYRUS MOLECULAR LAYER VOLUMETRIC CHANGES IN VALPROIC ACID MOUSE MODEL OF AUTISM SPECTRUM DISORDERS

2019 ◽  
Author(s):  
Alinne Lorrany Gomes Dos Santos ◽  
Luma Cristina Guerreiro Ferreira ◽  
Dilza Souza ◽  
Daniel Guerreiro Diniz ◽  
Cristovam Wanderley Picanço Diniz
Keyword(s):  
Valproic Acid ◽  
Autism Spectrum Disorders ◽  
Mouse Model ◽  
Dentate Gyrus ◽  
Molecular Layer ◽  
Autism Spectrum ◽  
Spectrum Disorders
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