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An Animal Model for the Fetal Valproate Syndrome

Thursday, 2 May 2013: 09:00-13:00
Banquet Hall (Kursaal Centre)
F. Bertelsen1,2, A. Møller1,2, A. M. Landau1,2, P. Weikop3, A. Sabers4 and J. Scheel-Krüger1, (1)Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark, (2)PET-centre, Aarhus University Hospital, Aarhus, Denmark, (3)Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Copenhagen, Denmark, (4)The Epilepsy Clinic, Department of Neurology, Rigshospitalet, Copenhagen, Denmark
Background: In the human clinic the fetal valproate syndrome is characterized by somatic malformations and cognitive dysfunctions, which include the autistic spectrum disorders.

Objectives: The objective of this study is to establish a novel animal model for autism induced by chronic, prenatal administration of the antiepileptic drug valproate (VPA) to pregnant rats.

Methods: Eighteen pregnant rats were exposed to daily clinically relevant doses of VPA or saline from the 12th day of pregnancy until birth. Neuropathological changes in the offspring were evaluated by stereology and presence of biomarkers in the prefrontal cortex, hippocampus and striatum. Behavioral changes relevant to autism were also investigated.

Results: We have found a significant increase in the number of neocortical cells in the offspring of the VPA rats compared to controls. Serotonin levels in the striatum of the VPA rats were significantly reduced compared to controls. Furthermore the male juvenile play behavior of VPA rats was reduced.  

Conclusions: The combined approach of histology, biochemistry and behavioral studies is necessary in the characterization and development of a novel rodent model of autism. Translational studies using this model may result in a better understanding of the developmental changes occurring during pregnancy and leading to autism in the human condition. A valid animal model is the first step in the testing of new drug candidates of interest for the pharmacological treatment of autism. This is of particular importance since the deficits in social behavior in autism are severely invalidating and no pharmacological compounds are currently available for the improvement or treatment of the devastating core behavioral symptoms.

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