A systematic review on Valproate induced rat model of autism: Pathophysiology, treatment, developmental and neurobehavioral assessment of rat offsprings


  • U Kavitha
  • E Kayalvizhi
  • K Revathy
  • T.R. Brindha
  • R Muthulakshmi
  • M Chandrasekar




Autism spectrum disorder, valporate induced animal model, neurobehaviour, neurodevelopmental reflex


Autism Spectrum disorder (ASD) is charecterised by certain degrees of disabilities in social communication, restrictive repetitive behaviour and altered motor and sensory perception. Translational research is carried out by creating animal models of autism to find out the correlation between behavioural changes and the pathology of brain tissue and for clinical trials of newer therapeutic formulations. Valproate induced animal model of autism has significant validity to demonstrate ASD manifestations. An early appreciation of ASD symptoms is needed for a better prognosis. So assessment of behavioural abnormalities and development stones in the first month of animal life are much important to study ASD.An extensive literature search was done on different databases. (PUBMED-MeSH, PMC, Webof Science, Google scholar and Research Gate). Original articles reported between the years 2000-2020 were selected. PRISMA protocol was followed. There are good quantities of studies on behavioural assessment of valproate induced animal model. This review explains the pathophysiology and various treatment modalities tried in valporate induced animal model and it also enlists the developmental and behavioural assessment methods of rat off springs. It will be useful to demonstrate all signs of autism.


Author Biographies

U Kavitha

Meenakshi Medical College Hospital & Research Institute, Kanchipuram, Tamil Nadu, India

K Revathy

Meenakshi Academy of Higher Education and Research, Chennai, Tamil Nadu, India

T.R. Brindha

Vel R.S Medical College, Chennai, Tamil Nadu, India

R Muthulakshmi

Meenakshi Medical College Hospital & Research Institute, Kanchipuram, Tamil Nadu, India

M Chandrasekar

Bharath University of Higher Education, Chennai, Tamil Nadu, India


Chauhan, A., Sahu, J.K., Jaiswal, N., Kumar, K., Agarwal,A., Kaur, J.,et al.,Prevalence of autism spectrum disorder in Indian children: a systematic review and meta-analysis. Neurology India. 2019 Jan 1;67(1):100.

Dubovický, M. Neurobehavioral manifestations of developmental impairment of the brain. Interdisciplinary Toxicology. 2010 Jun 1;3(2):59-67

Crawley, J.N. Designing mouse behavioral tasks relevant to autistic-like behaviors. Ment Retard Dev Disabil Res Rev.2011;10(4):248-258.

Arndt,T.L., Stodgell, C.J., Rodier, P.M. The teratology of autism. Int. J. Dev. Neurosci. 2005;23: 189–199.

Rodier, P.M. Converging evidence for brain stem injury in autism. Dev. Psychopathol. 2002; 14: 537–557.

Bambini,J.V., Rodrigues, L., Behr, G.A., Moreira, J.C., Riesgo, R., Gottfried, C. Animal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters. Brain research. 2011 Aug 23;1408:8-16.

Favre, M.R., Barkat, T.R., Mendola, D.L., Khazen, G., Markram, H., Markram, K. General developmental health in the VPA-rat model of autism. Frontiers in behavioral neuroscience. 2013 Jul 24;7:88.

Schneider, T., Roman, A., Basta-Kaim, A., Kubera, M., Budziszewska, B., Schneider, K.,et al., Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology. 2008 Jul 1;33(6):728-740.

Ornoy, A.Valproic acid in pregnancy:how are we endangering the embryo and fetus?Reprod.Toxicol. 2009;28:1–10.

Kim, K.C., Kim, P., Go, H.S., Choi, C.S., Yang, S.I., Cheong, J.H.,et al.,The critical period of valproate exposure to induce autistic symptoms in Sprague–Dawley rats. Toxicology letters. 2011 Mar 5;201(2):137-142.

Ogawa, T., Kuwagata, M., Hori, Y., Shioda, S. Valproate-induced developmental neurotoxicity is affected by maternal conditions including shipping stress and environmental change during early pregnancy. Toxicology letters. 2007 Nov 1;174(1-3):18-24.

Lin, H.C., Gean, P.W., Wang, C.C., Chan, Y.H., Chen, P.S. The amygdala excitatory/inhibitory balance in a valproate-induced rat autism model. PLos one. 2013 Jan 29;8(1):e55248.

Kim, K.C., Lee, D.K., Go, H.S., Kim, P., Choi, C.S., Kim, J.W.,et al., Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring. Molecular neurobiology. 2014 Feb 1;49(1):512-528.

Hadjikhani, N. Serotonin, pregnancy and increased autism prevelence: Is there a link? Med Hypothesis doi: 10.1016/j.mehy.2009.

Zhao, G., Gao, J., Liang, S., Wang, X., Sun, C., Xia, W.,et al., Study of the serum levels of polyunsaturated fatty acids and the expression of related liver metabolic enzymes in a rat valproate-induced autism model. Internationaal journal of developmental neuroscience. 2015 Aug 1;44:14-21.

Chakrabarti, B., Baron, C.S. Variation in the human cannabinoid receptor CNR1 gene modulates gaze duration for happy faces. Mol Autism. 2011; 2: 10.

Servadio, M., Melancia, F., Manduca, A., DiMasi, A., Schiavi, S., Cartocci, V.,etal., Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid. Translational Psychiatry. 2016 Sep;6(9):e902-.

Kohls, G., Chevallier, C., Troiani, V., Robert, T.S. Social ‘wanting’ dysfunction in autism: neurobiological underpinnings and treatment implications. Journal of Neurodevelopmental Disorders. 2012 Dec;4(1):1-20.

Schneider, T., Turczak, J., Przew?ocki, R. Environmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism. Neuropsychopharmacology. 2006 Jan;31(1):36-46.

Banji, D.,Banji, O.J., Abbagoni, S., Hayath, M.S., Kambam, S., Chiluka, V.L. Amelioration of behavioral aberrations and oxidative markers by green tea extract in valproate induced autism in animals. Brain research. 2011 Sep 2;1410:141-151.

Sandhya, T., Sowjanya, J., Veeresh, B. Bacopamonniera (L.) Wettst ameliorates behavioral alterations and oxidative markers in sodium valproate induced autism in rats. Neurochemical research. 2012 May 1;37(5):1121-31.

Gao, J., Wang, X., Sun, H., Cao, Y., Liang, S., Wang, H., et al.,Neuroprotective effects of docosahexaenoic acid on hippocampal cell death and learning and memory impairments in a valproic acid-induced rat autism model. International journal of developmental neuroscience. 2016 Apr 1;49:67-78.

Kim, P., Park, J.H., Kwon, K.J., Kim, K.C., Kim, H.J., Lee, J.M., et al.,Effects of Korean red ginseng extracts on neural tube defects and impairment of social interaction induced by prenatal exposure to valproic acid. Food and Chemical Toxicology. 2013 Jan 1;51:288-296.

Juybari, K.B., Sepehri, G., Meymandi, M.S., Shahrbabaki, S.S., Moslemizadeh, A., Saeedi, N., et al.,Sex dependent alterations of resveratrol on social behaviors and nociceptive reactivity in VPA-induced autistic-like model in rats. Neurotoxicology and Teratology. 2020 Jun 11:106905.

Scheggi, S., Guzzi, F., Braccagni, G., De Montis, M., Parenti, M., Gambarana, C.Targeting PPAR? in the rat valproic acid model of autism: focus on social motivational impairment and sex-related differences. Molecular Autism.2020; 11: 62.

Shiitu, B.S., Othman, F., Abdullah, F.F., Basri, H.,Eshak, Z. Preventive effect of Nigella sativaoil extract on neurobehavioural deficit induced by prenatal valproic acid exposure in mouse offsprings. Journal of Pharmaceutical, Chemical and Biological Sciences. 2017; 5(1):70-83

Cezar, L.C., Kirsten, T.B., Da Fonseca, C.C., de Lima, A. P, Bernardi, M. M., Felicio, L. F. Zinc as a therapy in a rat model of autism prenatally induced by valproic acid. Progress in neuro-psychopharmacology and biological psychiatry. 2018 Jun 8;84:173-180.

Al-Amin, M.M., Rahman, M.M., Khan, F.R., Zaman, F., Reza, H.M. Astaxanthin improves behavioral disorder and oxidative stress in prenatal valproic acid-induced mice model of autism. Behavioural brain research. 2015 Jun 1;286:112-21.

Huang, F., Chen, X., Jiang, X., Niu, J., Cui, C., Chen, Z., et al., Betaine ameliorates prenatal valproic?acid?induced autism?like behavioral abnormalities in mice by promoting homocysteine metabolism. Psychiatry and Clinical Neurosciences. 2019 Jun;73(6):317-22.

Philip, J., Bushnell, V.,Virgina, C., Robert, C.,Macphail, Wendy, M., OshiroEthel, C. Neurobehavioral assessments of rats perinatally exposed to a commercial mixture of polychlorinated biphenyls. Toxicological Sciences. 2002;68(1):109–120

Moogeh, B., Sanjeev, K.,Bhardwaj.,Lalit, K., Srivastava. Neonatal behavioral changes in rats with gestational exposure to lipopolysaccharide: a prenatal infection model for developmental neuropsychiatric disorders, Schizophrenia Bulletin.2012;38(3):444–456.

Fox, W.M. Reflex-ontogeny and behavioural development of the mouse Animal Behaviour.1965;13(2-3):234-241.

Forsingdal, A., Fejgin, K., Nielsen, V., Werge, T., Nielsen, J. 15q13.3 homozygous knockout mouse model display epilepsy- autism- and schizophrenia-related phenotypes. Transl Psychiatry. 2016;6(7):e860.

Nguyen, A.T., Armstrong, E.A., Yager, J.Y. Neurodevelopmental reflex testing in neonatal rat pups. J Vis Exp. 2017;(122):55261

Ali, A., Vasileva, S., Langguth, M., Suzanne, A., Xiaoying, C., Andrew,W., et al., Developmental vitamin d deficiency produces behavioral phenotypes of relevance to autism in an animal model. Nutrients. 2019;11(5):1187

Antunes,M., Biala,G., The novel object recognition memory: Neurobiology, test procedure, and its modifications. Cogn. Process. 2021;13:93-110.

Lins, B.R.,Hurtubise, J.L., Roebuck, A.J., Marks, W.N., Zabder, N.K., Scott, G.A., et al.,Prospective analysis of the effects of maternal immune activation on rat cytokines during pregnancy and behavior of the male offspring relevant to schizophrenia. ENeuro. 2018 Aug 14.

Deacon,R.M., Rawlins,J.N. T-maze alternation in the rodent. Nat Protoc. 2006;1(1):7-12.

Hall, B.J., Cauley, M., Burke, D.A., Kiany, A., Slotkin, T.A., Levin, E.D. Cognitive and behavioral impairments evoked by low-level exposure to tobacco smoke components: comparison with nicotine alone. Toxicol Sci. 2016;151(2):236-244.

Potasiewicz, A., Gzielo, K., Popik, P.Nikiforuk, A. Effects of prenatal exposure to valproic acid or poly (I: C) on ultrasonic vocalizations in rat pups: the role of social cues. Physiology &Behavior. 2020 Jul 30:113113.

Moy,S.S., Nadler,J.J.,Young, N.B., Nonneman, R.J., Segall, S.K., Andrade, G.M.,et al.,Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav. 2004;3(5):287-302.

Seibenhener, M.L., Wooten, M.C. Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice. J. Vis. Exp. 2015:e52434.




How to Cite

Kavitha U, Kayalvizhi E, Revathy K, Brindha T, Muthulakshmi R, Chandrasekar M. A systematic review on Valproate induced rat model of autism: Pathophysiology, treatment, developmental and neurobehavioral assessment of rat offsprings. Biomedicine [Internet]. 2021Apr.3 [cited 2021Apr.14];41(1):9-15. Available from: https://biomedicineonline.org/index.php/home/article/view/526