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      General developmental health in the VPA-rat model of autism

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          Abstract

          Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study the neuroanatomical, neurophysiological and molecular mediators in more detail and in a more controlled environment. The valproic acid (VPA) rat model is an environmentally triggered model with strong construct and clinical validity. It is based on VPA teratogenicity in humans, where mothers who are medicated with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we present our observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5, as well as their male and female offspring, in comparison to saline-exposed controls. We report increased rates of complete fetal reabsorption after both VPA doses. VPA 500 mg/kg showed no effect on dam body weight during pregnancy or, on litter size. Offspring exposed to VPA 500 mg/kg showed smaller brain mass on postnatal days 1 (P1) and 14 (P14), in addition to abnormal nest seeking behavior at P10 in the olfactory discrimination test, relative to controls. We also report increased rates of physical malformations in the offspring, rare occurrences of chromodacryorrhea and, developmentally similar body mass gain. Further documentation of developmental health may guide sub-grouping of individuals in a way to better predict core symptom severity.

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          Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism.

          Autism is a severe behavioral disorder characterized by pervasive impairments in social interactions, deficits in verbal and nonverbal communication, and stereotyped, repetitive patterns of behaviors and interests. Recently, a new rodent model of autism was created by exposure of rat fetuses to valproic acid (VPA) on the 12.5th day of gestation (VPA rats). The model has striking anatomical, pathological, and etiological similarities to human data; however, it has not been characterized behaviorally. In order to determine if VPA rats present behavioral aberrations observed in autism, their behavior was extensively evaluated in a battery of tests. The results of the present experiments demonstrate that VPA rats exhibit: (1) lower sensitivity to pain and higher sensitivity to nonpainful stimuli, (2) diminished acoustic prepulse inhibition, (3) locomotor and repetitive/stereotypic-like hyperactivity combined with lower exploratory activity, and (4) decreased number of social behaviors and increased latency to social behaviors. In addition, VPA rats showed delayed maturation, lower body weight, delayed motor development, and attenuated integration of a coordinated series of reflexes, delayed nest-seeking response mediated by olfactory system, and normal negative geotaxis. Interestingly, all behavioral aberrations described in this paper appear before puberty, which could distinguish the VPA rat model of autism from other animal models of neurodevelopmental disorders, especially rodent models of schizophrenia. Our results bring further support to validity of the proposed VPA animal model of autism, suggesting similarities between the observed pattern of behavioral alterations in VPA rats and features of disturbed behavior in autistic patients.
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            Autistic disturbances of affective contact.

            L Kanner (1968)
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              Brain growth across the life span in autism: age-specific changes in anatomical pathology.

              Autism is marked by overgrowth of the brain at the earliest ages but not at older ages when decreases in structural volumes and neuron numbers are observed instead. This has led to the theory of age-specific anatomic abnormalities in autism. Here we report age-related changes in brain size in autistic and typical subjects from 12 months to 50 years of age based on analyses of 586 longitudinal and cross-sectional MRI scans. This dataset is several times larger than the largest autism study to date. Results demonstrate early brain overgrowth during infancy and the toddler years in autistic boys and girls, followed by an accelerated rate of decline in size and perhaps degeneration from adolescence to late middle age in this disorder. We theorize that underlying these age-specific changes in anatomic abnormalities in autism, there may also be age-specific changes in gene expression, molecular, synaptic, cellular, and circuit abnormalities. A peak age for detecting and studying the earliest fundamental biological underpinnings of autism is prenatal life and the first three postnatal years. Studies of the older autistic brain may not address original causes but are essential to discovering how best to help the older aging autistic person. Lastly, the theory of age-specific anatomic abnormalities in autism has broad implications for a wide range of work on the disorder including the design, validation, and interpretation of animal model, lymphocyte gene expression, brain gene expression, and genotype/CNV-anatomic phenotype studies. Copyright © 2010 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Front Behav Neurosci
                Front Behav Neurosci
                Front. Behav. Neurosci.
                Frontiers in Behavioral Neuroscience
                Frontiers Media S.A.
                1662-5153
                24 July 2013
                2013
                : 7
                : 88
                Affiliations
                [1] 1Laboratory of Neural Microcircuits, Brain Mind Institute, École Polytechnique Fédérale de Lausanne Lausanne, Switzerland
                [2] 2Department of Neuroscience and Pharmacology, Copenhagen University Copenhagen, Denmark
                [3] 3Computer Science and Mathematics Department, School of Arts and Sciences, Lebanese American University Byblos, Lebanon
                Author notes

                Edited by: Nuno Sousa, University of Minho, Portugal

                Reviewed by: Edward S. Brodkin, Perelman School of Medicine at University of Pennsylvania, USA; Jane A. Foster, McMaster University, Canada

                *Correspondence: Kamila Markram, Brain Mind Institute-SV-Laboratory of Neural Microcircuits, École Polytechnique Fédérale de Lausanne, Station 15, 1015 Lausanne, Switzerland e-mail: kamila.markram@ 123456epfl.ch
                Article
                10.3389/fnbeh.2013.00088
                3721005
                23898245
                c6e67cd9-d045-485d-b9d2-2f324397ca94
                Copyright © 2013 Favre, Barkat, LaMendola, Khazen, Markram and Markram.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 01 May 2013
                : 01 July 2013
                Page count
                Figures: 4, Tables: 3, Equations: 0, References: 102, Pages: 11, Words: 10045
                Categories
                Neuroscience
                Original Research Article

                Neurosciences
                autism,valproic acid,vpa,animal model,rat,teratogen,development
                Neurosciences
                autism, valproic acid, vpa, animal model, rat, teratogen, development

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