Social behavior, neuroimmune markers and glutamic acid decarboxylase levels in a rat model of valproic acid-induced autism

Abstract

Autism is a complex neurodevelopmental disorder characterized by impaired social communication and social interactions, and repetitive behaviors. The etiology of autism remains unknown and its molecular basis is not yet well understood. Pregnant Sprague-Dawley (SD) rats were administered 600 mg/kg of valproic acid (VPA) by intraperitoneal injection on day 12.5 of gestation. Both 11-to 13-week-old male and female rat models of VPA-induced autism showed impaired sociability and impaired preference for social novelty as compared to the corresponding control SD rats. Significantly reduced mRNA expressions of social behavior-related genes, such as those encoding the serotonin receptor, brain-derived neurotrophic factor and neuroligin3, and significantly increased expression levels of proinflammatory cytokines, such as interleukin-1 β and tumor necrosis factor-α, were noted in the hippocampi of both male and female rats exposed to VPA in utero. The hippocampal expression level of gamma amino butyric acid (GABA) enzyme glutamic acid decarboxylase (GAD) 67 protein was reduced in both male and female VPA-exposed rats as compared to the corresponding control animals. Our results indicate that developmental exposure to VPA affects the social behavior in rats by modulating the expression levels of social behavior-related genes and inflammatory mediators accompanied with changes in GABA enzyme in the hippocampus.

Perinatal exposure to diesel exhaust origin secondary organic aerosol induces autism-like behavior in rats

“…Critical window for occurrence of childhood ASD was third trimester of pregnancy [13,56,57] Sex-speci c effects were observed in ASD and boys are 5 times greater risk for ASD than girls. In our previous study, impairment of social behavior and related gene expression changes were prominent in male rats of VPA-induced autism model [28]. In the present study, we found remarkable activation of mast cell and microglia in the prefrontal cortex of male rats exposed to DE-SOA.…”

“…Recently we have reported that developmental VPA and arsenic exposure impaired social behavior by modulating serotonin receptors and decreasing BDNF [28,43]. In the present study, we found downregulation of mRNA expression levels of social behavior related gene serotonin receptor 5HT5B and neurotrophic factors BDNF in the prefrontal cortex of male and female rats exposed to DE-SOA.…”

“…It was reported that gestational exposure to valproate have 8-fold increased risk to have ASD in children [41,42]. Previously, we have demonstrated that developmental exposure to valproic acid induced poor social behavior in adult rats by modulating the expression levels of social behavior-related genes and in ammatory mediators accompanied with changes in GABA enzyme glutamic acid decarboxylase 67 (GAD67) in the hippocampus [28]. In that study we have showed that GAD67 de ciency may be associated with glutamate/GABA imbalance in autistic brain.…”

“…Microglial activation in the prefrontal cortex was examined. The tissue sections were stained with microglial marker Iba1 as described previously [28]. Brie y, the brain sections were immersed in absolute ethanol, followed by 10% H 2 O 2 for 10 min each at room temperature.…”

“…In addition, we have showed that early life exposure to DE-SOA impaired social behavior and alteration in social behavior related gene expression in the hypothalamus of adult male BALB/c mice [27]. Recently, we have developed valproic acid (VPA)-induced autism model rats and showed that reduction of gamma amino butyric acid (GABA) synthetic enzyme glutamic acid decarboxylase (GAD) 67 protein in both male and female VPA-exposed rats resulting in imbalance of glutamate/GABA was the possible mechanism for ASD [28].…”