Effects of Rat Prenatal Exposure to Valproic Acid on Behaviour and Neuro-Anatomy

Abstract

Autism is a highly debilitating disorder that has recently displayed a dramatic rise in incidence. In order to realistically study preventative and remedial strategies, it is important that we develop and understand useful animal models of the disorder. The purpose of this study was to investigate the efficacy of the prenatal valproic acid (VPA) rat model of autism by examining the neuro-anatomical and behavioural outcomes of offspring exposed to this paradigm. The VPA-treated rats exhibited behavioural changes in the delayed non-match-to-sample task, novel object recognition, activity box, and Whishaw tray reaching task. Anatomically, there was a reduction in brain weight and cortical thickness, along with decreased dendritic branching in the orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), and decreased spine density in the mPFC, OFC, and cerebellum. Behavioural and anatomical findings from this study produced reliable results indicating that prenatal VPA exposure may be a viable model for the study of autism in rats.

Orbitofrontal cortex 5-HT2A receptor mediates chronic stress-induced depressive-like behaviors and alterations of spine density and Kalirin7

“…Decreased dendritic spines density and dendritic branching in the mPFC, OFC or dorsolateral PFC are associated with psychiatric disorders including autism (Mychasiuk et al, 2012), schizophrenia and bipolar disorder (Konopaske et al, 2014) . The same alterations have been occurred in the mPFC following chronic stress (Goldwater et al, 2009, Radley et al, 2013, despite apical dendritic hypertrophy in the OFC after chronic restraint stress (Liston et al, 2006).…”

Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism

“…Prenatal exposure to valproic acid (VPA) is a well-validated animal model of autism, since it mimics major behavioral and neuroanatomical alterations found in ASD [30,31,32]. Early reports on the VPA model showed cerebellar and brainstem alterations similar to those seen in ASD patients [30,33], along with reduced social interaction and increased repetitive behaviors [31].…”

“…The VPA model has become an excellent tool for exploring candidate brain areas likely to be implicated in the behavioral phenotype of ASD [34]. Most recently, research has focused on the medial prefrontal cortex (mPFC) of VPA animals, where hyperconnectivity, increased long-term potentiation and changes in dendritic arborization across different developmental periods have been revealed [32,35,36,37,38,39]. However, characterization of the cytoarchitectural, glial and synaptic profiles in the mPFC is still missing.…”

Recent advances in animal model experimentation in autism research

“…Effects of treatment References VPA Prenatal exposure of VPA in rodents produces neuroanatomical and behavioural deficits and alters social behaviours. VPA exposure in rats lowers neurons and alters neuronal morphology, and produces an imbalance of oxidative homeostasis that facilitates susceptibility to autism (22)(23)(24)(25)(26)(27)(28)(29)(30) PPA ICV injections of PPA results in brain and behavioural abnormalities in rats, generates neuroinflammatory response, increases oxidative stress, which are linked to autistic behaviour (31)(32)(33) ICV, intracerebroventricular; PPA, propionic acid; VPA, valproic acid. Propionic acid (PPA).…”