Evaluating the role of maternal separation stress on the development of autistic-like behaviour in Sprague-Dawley rats.

Abstract

Autism Spectrum Disorders (ASD) are a category of neurodevelopmental disorders that have become more prevalent, causing much concern. Autistic individuals display symptoms ranging from repetitive behaviours to communication deficiency and impaired executive function. There are numerous risk factors for autism including exposure to particular medications, like valproic acid (VPA), and certain environments. VPA has been shown to increase the risk of autism in unborn children. Furthermore, early stressful events like maternal deprivation are known to have a part in causing neurodevelopmental disorders. Therefore, in this study we used VPA to induce autism and aimed at investigating how VPA alters the major neurotransmitter system pathways, which results in autistic-like behaviour. Furthermore, we conducted maternal separation to investigate the effect of stress together with VPA. This study used forty-eight Sprague-Dawley rat pups which were divided in to control (saline-0.9%, 3.3 ml/kg), VPA (VPA-500 mg/kg) and stressed groups. Maternal separation stress was conducted for 12 days. The novel-object recognition test and open field test were conducted to assess the pup’s behaviour. PCR was conducted to measure the expression of GABA receptors in the hippocampus and cerebellum. The concentrations of glutamate, serotonin transporter and corticosterone were assessed in the prefrontal cortex, hippocampus, amygdala and blood. Exposure to VPA resulted in decreased glutamate concentrations in the hippocampus and prefrontal cortex whilst it caused an increase in hippocampal GABBR1, GABRB3 and cerebellum GABRB3, but a decrease in the cerebellum GABBR1. These alterations were accompanied by repetitive and hyperactive behaviour, seen in the open field test whilst memory deficits were observed in the novel object recognition test. Exposure to maternal separation stress and VPA caused a dysfunction in the stress response which lead to a decrease in corticosterone concentration. Maternal separation stress and VPA exposure also decreased the serotonin transporter concentration in the amygdala and prefrontal cortex. These alterations were accompanied by anxiety-like behaviours, seen in the open field test where we observed a decrease in the time spent in the centre and the total excretion. This study shows that exposure to VPA alters neurotransmitter balance thus resulting in an autistic-like phenotype. Furthermore, exposure to maternal separation stress and VPA causes a desensitization in the stress response.