Skip to main content
SpringerLink
Log in

A New Neurobehavioral Model of Autism in Mice: Pre- and Postnatal Exposure to Sodium Valproate

  • ORIGINAL PAPER
  • Published:
Journal of Autism and Developmental Disorders Aims and scope Submit manuscript

Abstract

Autism symptoms, including impairments in language development, social interactions, and motor skills, have been difficult to model in rodents. Since children exposed in utero to sodium valproate (VPA) demonstrate behavioral and neuroanatomical abnormalities similar to those seen in autism, the neurodevelopmental effects of this antiepileptic agent were examined in mice following its pre- or postnatal administration. Exposed pups were evaluated in a battery of neurodevelopmental procedures designed to assess VPA-induced retardation (wherein a behavior fails to mature on schedule), regression (wherein a behavior does mature on time but then deteriorates), or intrusions (wherein normal behaviors are overshadowed by stereotypic or self-injurious behaviors). The resulting observations were interpreted in the context of this new strategy to model autism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15

Similar content being viewed by others

References

  • Allen, S. M., & Davis, W. M. (1999). Relationship of dopamine to serotonin in the neonatal 6-OHDA rat model of Lesch-Nyhan syndrome. Behavioral Pharmacology, 10, 467–474.

    Article  Google Scholar 

  • Ardinger, H. H., Atkin, J. F., Blackston, D., Elsas, L. J., Clarren, S. K., Livingstone, S., Flannery, D. B., Pellock, J. M., Harrod, M. J., Lammer, E. J., Majewski, F., Schnizel, A., Toriello, H. V., & Hanson, J. W. (1988). Verification of the fetal valproate syndrome phenotype. American Journal Medical Genetics, 29, 171–185.

    Article  Google Scholar 

  • Aylward, E. H., Minshew, N. J., Goldstein, G., Honeycutt, N. A., Augustine, A. M., Yates, K. O., Barta, P. E., & Pearlson, G. D. (1999). MRI volumes of amygdale and hippocampus in non-mentally retarded autistic adolescents and adults. Neurology, 53, 2145–2150.

    PubMed  Google Scholar 

  • Bachevalier, J., & Beauregard, M. (1993). Maturation of medial temporal lobe memory functions in rodents, monkeys, and humans. Hippocampus, 3, 191–202.

    PubMed  Google Scholar 

  • Bauman, M., & Kemper, T. L. (1985). Histoanatomic observations of the brain in early infantile autism. Neurology, 35, 866–874.

    PubMed  Google Scholar 

  • Chapman, J. B., & Cutler, M. G. (1989). Effects of sodium valproate on development and social behaviour in the Mongolian gerbil. Neurotoxicolology & Teratology, 11, 193–198.

    Article  Google Scholar 

  • Coldren, J. T., & Halloran, C. (2003). Spatial reversal as a measure of executive functioning in children with autism. Journal of Genetic Psychology, 164, 29–41.

    Article  PubMed  Google Scholar 

  • Courchesne, E. (1997). Brainstem, cerebellar and limbic neuranatomical abnormalities in autism. Current Opinion in Neurobiology, 7, 269–278.

    Article  PubMed  Google Scholar 

  • Courchesne, E., Karns, C. M., Davis, H. R., Ziccardi, R., Carper, R., Tigue, Z., Chisum, H. J., Moses, P., Pierce, K., Lord, C., Lincoln, A. J., Pizzo, S., Schreibman, L., Haas, R. H., Akshoofoff, N. A., & Courchesne, R. Y. (2001). Unusual brain growth patterns in early life in patients with autistic disorder: And MRI study. Neurology, 57, 245–254.

    PubMed  Google Scholar 

  • Duva, C. A., Floresco, S. B., Wunderlich, G. R., Lao, T. L., Pinel, J. P., & Phillips, A. G. (1997). Disruption of spatial but not object-recognition memory by neurotoxic lesions of the dorsal hippocampus in rats. Behavioral Neuroscience, 111, 1184–1196.

    Article  PubMed  Google Scholar 

  • Fatemi, S. H., Halt, A. R., Realmuto, G., Earle, J., Kist, D. A., Thuras, P., & Merz, A. (2002). Purkinje cell size is reduced in the cerebellum of patients with autism. Cellular and Molecular Neurobiology, 22, 171–175.

    Article  PubMed  Google Scholar 

  • Galini, R., Weiss, I., Cassel, J. C., & Kelche, C. (1998). Spatial memory, habituation and reactions to spatial and non-spatial changes in rats with selective lesions of the hippocampus, the entorhinal cortex or the subiculum. Behavioral Brain Research, 96, 1–12.

    Article  Google Scholar 

  • Gallagher, M., & Holland, P. C. (1992). Preserved configural learning and spatial learning impairment in rats with hippocampal damage. Hippocampus, 2, 81–88.

    Article  PubMed  Google Scholar 

  • Goldberg, M. C., Landa, R., Lasker, A., Cooper, L., & Zee, D. S. (2000). Evidence of normal cerebellar control of the vestibule-ocular reflex (VOR) in children with high-functioning autism. Journal of Autism and Developmental Disorders, 30, 519–524.

    Article  PubMed  Google Scholar 

  • Goldman, P. S. (1971). Functional development of the prefrontal cortex in early life and the problem of neuronal plasticity. Experimental Neurology, 32, 366–387.

    Article  PubMed  Google Scholar 

  • Good, M., & Honey, R. C. (1997). Dissociable effects of selective lesions to hippocampal subsystems on exploratory behavior, contextual learning and spatial learning. Behavioral Neuroscience, 111, 487–493.

    Article  PubMed  Google Scholar 

  • Haberer, L. J., & Pollack, G. M. (1994). Disposition and protein binding of valproic acid in the developing rat. Drug Metabolism and Disposition, 22, 113–119.

    PubMed  Google Scholar 

  • Halladay, A. K., Kusnecov, A., Michna, L., Kita, T., Hara, C. & Wagner, G. C. (2003). Relationship between methamphetamine-induced dopamine release, hyperthermia, self-injurious behaviour and long-term dopamine depletion in BALB/c and C57BL/6 mice. Pharmacology & Toxicology, 93, 33–41.

    Article  Google Scholar 

  • Halladay, A. K., Wagner, G. C., Zhou, R., & Reuhl, K. R. (2004). Neurodevelopmental consequences of MeHg in an animal model of autism. Hawaii Neurotoxicology Conference.

  • Herbert, M. R., Ziegler, D. A., Deutsch, C. K., O’Brien, L. M., Lange, N., Bakardjiev, A., Hodgson, J., Adrien, K. T., Steele, S., Makris, N., Kennedy, D., Harris, G. J., & Caviness, V. S. (2003). Dissociations of cerebral cortex, subcortical and cerebral white matter volumes in autistic boys. Brain, 126, 1181–1192.

    Article  Google Scholar 

  • Ingram, J. L., Peckharm, S. M., Tisdale, B., & Rodier, P. M. (2000). Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicology & Teratology, 22, 319–324.

    Article  Google Scholar 

  • Inouye, M. & Murakami, U. (1980). Temporal and spatial patterns of Purkinje cell formation in the mouse cerebellum. Journal of Comparative Neurology, 194(3), 499–503.

    Article  PubMed  Google Scholar 

  • Jinnah, H. A., Gage, F. H., & Friedmann, T. (1990). Animal models of Lesch-Nyhan Syndrome. Brain Research Bulletin, 25, 467–475.

    Article  PubMed  Google Scholar 

  • Kates, W. R., Mostofsky, S., Zimmerman, A. W., Mazzocco, M. M., Landa, R., Warsofsky, I. S., Kaufmann, W. E., & Reiss, A. L. (1998). Neuroanatomical and neurocognitive differences in a pair of monozygotic twins discordant for strictly defined autism. Annals of Neurology, 43, 782–791.

    Article  PubMed  Google Scholar 

  • Kelly, P. H., Sevoir, P. W., & Iversen, S. D. (1975). Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Research, 94, 507–522.

    Article  PubMed  Google Scholar 

  • Kimble, D. P., Kirkby, R. J., & Stein, D. G. (1966). Response perseveration interpretation of passive avoidance deficits in hippocampectomized rats. Journal of Comparative and Physiological Psychology, 61, 141–143.

    Article  PubMed  Google Scholar 

  • Koch, S., Jager-Roman, E., Losche, G., Nau, H., Rating, D., & Helge, H. (1996). Antiepileptic drug treatment in pregnancy: Drug side effects in the neonate and neurological outcome. Acta Paediatricia, 84, 739–746.

    Article  Google Scholar 

  • Luna, B., Minshew, N. J., Garver, K. E., Lazar, N. A., Thulborn, K. R., Eddy, W. F., & Sweeney, J. A. (2002). Neocortical system abnormalities in autism. An fMRI study of spatial working memory. Neurology, 59, 834–840.

    PubMed  Google Scholar 

  • Mawer, G., Clayton-Smith, J., Coyle, H., & Kini, U. (2002). Outcome of pregnancy in women attending an outpatient epilepsy clinic: Adverse features associated with higher doses of sodium valproate. Seizure, 692, 1–7.

    Google Scholar 

  • Miller, E. A., Goldman, P. S., & Rosvold, H. E. (1973). Delayed recovery of function following orbital prefrontal lesions in infant monkeys. Science, 182, 304–306.

    Article  PubMed  Google Scholar 

  • Moore, S. J., Turnpenny, P., Quinn, A., Glover, S., Lloyd, D. J., Montgomery, T., & Dean, J. C. S. (2000). A clinical study of 57 children with fetal anticonvulsant syndromes. Journal of Medical Genetics, 37, 489–497.

    Article  PubMed  Google Scholar 

  • Morris, R. G., Schenk, F., Tweedie, F., & Jarrard, L. E. (1990). Ibotenate lesions of hippocampus and/or subiculum: Dissociating components of allocentric spatial learning. European Journal of Neuroscience, 2, 1016–1028.

    Article  PubMed  Google Scholar 

  • Mueller, K., Saboda, S., Palmour, R., & Nyhan, W. L. (1982). Self-injurious behavior produced in rats by daily caffeine and continuous amphetamine. Pharmacology, Biochemistry & Behavior, 17, 613–617.

    Article  Google Scholar 

  • Muller, R. A., Pierce, K., Ambrose, J. B., Allen, G., & Courchesne, E. (2001). Atypical patterns of cerebral motor activiation in autism: A functional magnetic resonance study. Biological Psychiatry, 49, 665–676.

    Article  PubMed  Google Scholar 

  • Oliviera, M. G., Bueno, O. F., Pomarico, A. C., & Gugliano, E. B. (1997). Strategies used by hippocampal- and caudate-putamen-lesioned rats in a learning task. Neurobiology of Learning & Memory, 68, 32–41.

    Article  Google Scholar 

  • Packard, M. G., & Teather, L. A. (1997). Double dissociation of hippocampal and dorsal-striatal memory systems by posttraining intracerebral injections of 2-amino-5-phosphonopentaonic acid. Behavioral Neuroscience, 111, 543–551.

    Article  PubMed  Google Scholar 

  • Petrosini, L., Molinari, M., & Gremoli, T. (1990). Hermicerebellectomy and motor behavior in rats. I. Development of motor function after neonatal lesion. Experimental Brain Research, 82, 472–482.

    Article  Google Scholar 

  • Pierce, K., & Courchesne, E. (2001). Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biological Psychiatry, 49, 655–664.

    Article  PubMed  Google Scholar 

  • Pierce, K., Muller, R.A., Ambrose, J., Allen, G., & Courchesne, E. (2001). Face processing occurs outside the fusiform ‘face area’ in autism: Evidence from functional MRI. Brain, 124, 2059–2073.

    Article  PubMed  Google Scholar 

  • Rice, D., & Barone, S. (2000). Critical periods of vulnerability for the developing nervous system: Evidence from human and animal models. Environmental Health Perspective, 108, 511–533.

    Article  Google Scholar 

  • Sandi, C., Rose, S. P., & Patterson, T. A. (1992). Unilateral hippocampal lesions prevent recall of a passive avoidance task in day-old chicks. Neuroscience Letters, 141, 255–258.

    Article  PubMed  Google Scholar 

  • Sears, L. L., Vest, C., Mohamed, S., Bailey, J., Ranson, B. J., & Piven, J. (1999). An MRI study of the basal ganglia in autism. Progress in Neuropsychopharmacology & Biological Psychiatry, 23, 613–624.

    Article  Google Scholar 

  • Shishido, T., Watanabe, Y., Kato, K., Horikoshi, R., & Niwa, S. I. (2000). Effects of dopamine, NMDA, opiate, and serotonin-related agents on acute methamphetamine-induced self-injurious behavior in mice. Pharmacology, Biochemistry & Behavior, 66, 579–583.

    Article  Google Scholar 

  • Sobaniec-Lotoweska, M. E. (2001). Ultrastructure of purkinje cell perikara and their dendritic processes in the rat cerebellar cortex in experimental encephalopathy induced by chronic application of valproate. International Journal Experimental Pathology, 82, 337–348.

    Article  Google Scholar 

  • Sparks, B. F., Friedman, S. D., Shaw, D. W., Aylward, E. H., Echelard, D., Artru, A. A., Maravilla, K. R., Giedd, J. N., Munson, J., Dawson, G., & Dager, S. R. (2002). Brain structural abnormalities in young children with autism spectrum disorder. Neurology, 59, 184–192.

    PubMed  Google Scholar 

  • Sweeten, T. L., Posey, D. J., Shekhar, A., & McDougle, C. J. (2002). The amygdale and related structures in the pathopysiology of autism. Pharmacology, Biochemistry & Behavior, 71, 449–455.

    Article  Google Scholar 

  • Thullier, F., Lalonde, R., Mahler, P., Joyal, C. C., & Lestienne, F. (1996). Dorsal striatal lesions in rats. 2: Effects on spatial and non-spatial learning. Archives of Physiological Biochemistry, 104, 307–312.

    Article  Google Scholar 

  • Voorhees, C. V. (1986). Handbook of behavioral teratology. New York: Plenum Press.

    Google Scholar 

  • Voorhees, C. V. (1987). Behavioral teratogenicity of valproic acid: Selective effects on behavior after prenatal exposure to rats. Psychopharmacology, 92, 173–179.

    Article  PubMed  Google Scholar 

  • Wallace, R. B., Kaplan, R., & Werboff, J. (1977). Hippocampus and behavioral maturation. International Journal of Neuroscience, 7, 185–200.

    Article  PubMed  Google Scholar 

  • Williams, G., King, J., Cunningham, M., Stephan, M., Kerr, B., & Hersh, J. H. (2001). Fetal valproate syndrome and autism: Additional evidence of an association. Developmental Medicine and Child Neurology, 43, 202–206.

    Article  PubMed  Google Scholar 

  • Winocur, G. (1997). Hippocampal lesions alter conditioning to conditional and contextual stimuli. Behavioral Brain Research, 88, 219–229.

    Article  Google Scholar 

  • Wolf, L. W., LaRegina, M. C., & Tolbert, D. L. (1996). A behavioral study of the development of hereditary cerebellar ataxia in the shaker rat mutant. Behavioral Brain Research, 75, 67–81.

    Article  Google Scholar 

  • Wu, Y., & Wang, L. (2002). The effects of antiepileptic drugs on spatial learning and hippocampal protein kinase C ( in immature rats. Brain Development, 24, 82–87.

    Article  PubMed  Google Scholar 

  • Wong, W., Kumar, S., Rurak, D. W., Kwan, E., Abbott, F. S., & Riggs, K. W. (2000). Ontogeny of valproic acid disposition and metabolism: A developmental study in postnatal lambs and adult sheep. Drug Metabolism and Disposition, 28, 912–919.

    PubMed  Google Scholar 

  • Yu, S. Y., Sugiyama, Y., & Hanano, M. (1985). Changes in pharmacokinetics of valproic acid in guinea pigs from birth to maturity. Epilepsia, 26, 243–251.

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by: NS043981, ES05022, ES07148, ES11256, NJ Governor’s Council on Autism, and Johnson & Johnson.

Author information

Authors and Affiliations

  1. Department of Psychology, Rutgers University, New Brunswick, New Jersey, USA

    George C. Wagner & Paulette McRae

  2. Department of Pharmacology and Toxicology, Rutgers University, New Brunswick, New Jersey, USA

    Kenneth R. Reuhl & Alycia K. Halladay

  3. Department of Neuroscience, Rutgers University, New Brunswick, New Jersey, USA

    Michelle Cheh

  4. Center for Childhood Neurotoxicology and Exposure Assessment, Rutgers University, New Brunswick, New Jersey, 08854, USA

    George C. Wagner & Kenneth R. Reuhl

Authors
  1. George C. Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenneth R. Reuhl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michelle Cheh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paulette McRae
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alycia K. Halladay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George C. Wagner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wagner, G.C., Reuhl, K.R., Cheh, M. et al. A New Neurobehavioral Model of Autism in Mice: Pre- and Postnatal Exposure to Sodium Valproate . J Autism Dev Disord 36, 779–793 (2006). https://doi.org/10.1007/s10803-006-0117-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10803-006-0117-y

Keywords

Search

Navigation