Metabolomics profiling of valproic acid-induced symptoms resembling autism spectrum disorders using 1H NMR spectral analysis in rat model

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.

Download Full-text

Rat Model of Autism Spectrum Disorders

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2001.tb03640.x ◽

2006 ◽

Vol 939 (1) ◽

pp. 318-319 ◽

Cited By ~ 9

Author(s):

M.V. PLETNIKOV ◽

M.L. JONES ◽

S.A. RUBIN ◽

T.H. MORAN ◽

K.M. CARBONE

Keyword(s):

Autism Spectrum Disorders ◽

Rat Model ◽

Autism Spectrum ◽

Spectrum Disorders

Download Full-text

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

10.26226/morressier.5d1a036257558b317a13f855 ◽

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

Download Full-text

Beyond Genes: Germline Disruption in the Etiology of Autism Spectrum Disorders

Journal of Autism and Developmental Disorders ◽

10.1007/s10803-021-05304-1 ◽

2021 ◽

Author(s):

Jill Escher ◽

Wei Yan ◽

Emilie F. Rissman ◽

Hsiao-Lin V. Wang ◽

Arturo Hernandez ◽

...

Keyword(s):

Valproic Acid ◽

Autism Spectrum Disorders ◽

Sex Ratio ◽

Dna Sequence ◽

Autism Spectrum ◽

Anesthetic Gases ◽

Synthetic Steroids ◽

Spectrum Disorders ◽

And Behavior ◽

Developmental Exposures

AbstractInvestigations into the etiology of autism spectrum disorders have been largely confined to two realms: variations in DNA sequence and somatic developmental exposures. Here we suggest a third route—disruption of the germline epigenome induced by exogenous toxicants during a parent’s gamete development. Similar to cases of germline mutation, these molecular perturbations may produce dysregulated transcription of brain-related genes during fetal and early development, resulting in abnormal neurobehavioral phenotypes in offspring. Many types of exposures may have these impacts, and here we discuss examples of anesthetic gases, tobacco components, synthetic steroids, and valproic acid. Alterations in parental germline could help explain some unsolved phenomena of autism, including increased prevalence, missing heritability, skewed sex ratio, and heterogeneity of neurobiology and behavior.

Download Full-text

Pengaruh Pengayaan Lingkungan terhadap Gejala Autistic Like Behavior, Uji Experimental Pada Tikus

Jurnal Kesehatan Andalas ◽

10.25077/jka.v9i1s.1153 ◽

2020 ◽

Vol 9 (1S) ◽

Author(s):

Dinda Puan Rizka Wiranti ◽

Amel Yanis ◽

Deddy Saputra Saputra

Keyword(s):

Valproic Acid ◽

Autism Spectrum Disorders ◽

Normal Saline ◽

Autism Spectrum ◽

Closed Circuit ◽

Closed Circuit Television ◽

Post Test ◽

Spectrum Disorders

Pengobatan untuk Autism Spectrum Disorders (ASD) belum ditemukan saat ini. Paparan Valproic Acid (VPA) pada ibu hamil merupakan faktor lingkungan terjadinya ASD pada anak. Patomekanisme diduga adanya gangguan sinaps. Mayoritas orang tua anak ASD mengalami peningkatan stres kronis yang dapat berdampak pada kesehatan fisik dan emosional karena menyebabkan beban sosial dan finansial. Penelitian sebelumnya menemukan aktivitas neuronal bisa distimulasi melalui pengayaan lingkungan. Tujuan: Mengetahui pengaruh pengayaan lingkungan terhadap gejala Autistic Like Behavior (ALB); penurunan interaksi sosial dan peningkatan gerakan repetitif. Metode: Penelitian ini merupakan studi eksperimental laboratorik dengan one group pretest post test without control. Sampel terdiri dari 6 ekor tikus Spraque Dawley (SD) yang diinjeksikan dengan VPA 500 mg/kgBB intraperitoneal yang dilarutkan dalam normal saline menjadi 1.5 ml, kemudian diambil enam ekor anak tikus usia tiga minggu yang mempunyai gejala ALB dan dipindahkan ke kandang pengayaan lingkungan selama empat minggu. Pengamatan dilakukan menggunakan Closed Circuit Television (CCTV). Analisis data menggunakan uji t-berpasangan. Hasil: Analisis data didapatkan hasil uji t-berpasangan pada perilaku interaksi sosial dan gerakan repetitif adalah p=0.001 dan p= 0.003. Simpulan: Ada perbedaan yang signifikan perilaku interaksi sosial dan gerakan repetitif hewan coba sebelum dan sesudah pemberian pengayaan lingkungan selama 4 minggu.

Download Full-text

Altered Relationship Between Parvalbumin and Perineuronal Nets in an Autism Model

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.597812 ◽

2021 ◽

Vol 14 ◽

Author(s):

Dan Xia ◽

Li Li ◽

Binrang Yang ◽

Qiang Zhou

Keyword(s):

Valproic Acid ◽

Autism Spectrum Disorders ◽

Prefrontal Cortex ◽

Autism Spectrum ◽

Inhibitory Neurons ◽

Perineuronal Nets ◽

Spectrum Disorders ◽

Reduced Density ◽

The Relationship

Altered function or presence of inhibitory neurons is documented in autism spectrum disorders (ASD), but the mechanism underlying this alternation is poorly understood. One major subtype of inhibitory neurons altered is the parvalbumin (PV)-containing neurons with reduced density and intensity in ASD patients and model mice. A subpopulation of PV+ neurons expresses perineuronal nets (PNN). To better understand whether the relationship between PV and PNN is altered in ASD, we measured quantitatively the intensities of PV and PNN in single PV+ neurons in the prelimbic prefrontal cortex (PrL-PFC) of a valproic acid (VPA) model of ASD at different ages. We found a decreased PV intensity but increased PNN intensity in VPA mice. The relationship between PV and PNN intensities is altered in VPA mice, likely due to an “abnormal” subpopulation of neurons with an altered PV-PNN relationship. Furthermore, reducing PNN level using in vivo injection of chondroitinase ABC corrects the PV expression in adult VPA mice. We suggest that the interaction between PV and PNN is disrupted in PV+ neurons in VPA mice which may contribute to the pathology in ASD.

Download Full-text