A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

Abstract

Rationale Rodents exposed to valproic acid (VPA) in prenatal life exhibit post-natal characteristics analogous to autism spectrum disorder (ASD). Many previous studies used relatively high doses of VPA during early pregnancy, potentially confounding interpretation because the offspring are the "survivors" of a toxic insult. Low dose or late gestation exposure has not been widely studied. Objectives We examined the behavioral sequelae of late gestation exposure to low dose VPA in the mouse. We also examined postnatal levels of glutamic acid decarboxylase (GAD65 and GAD67) as markers for GABA neurons, because GABA pathology and subsequent excitatory/inhibitory imbalance is strongly implicated in ASD. Methods Pregnant C57BL/6N mice received a single subcutaneous injection of 100 or 200 mg/kg on gestation day 17. The control group received a saline injection on the same day. The offspring were tested in a battery of behavioral tests in adolescence and adulthood. Six brain regions were harvested and GAD65 and GAD67 were measured by western blotting. Results Compared to saline-exposed controls, adult mice exposed to prenatal VPA had impaired novel object exploration and fear conditioning anomalies. GAD67 was decreased in midbrain, olfactory bulb, prefrontal cortex and increased in cerebellum, hippocampus and striatum; GAD65 was decreased in all 6 regions. ConclusionsOur results suggest that a low dose of VPA in late pregnancy has persistent effects on brain development, and in particular the GABA system, which 3 may be relevant to ASD. Further attention to the impact of gestation time and dose of exposure in VPA-induced ASD models is encouraged.

Poly(I:C) Challenge Alters Brain Expression of Oligodendroglia-Related Genes of Adult Progeny in a Mouse Model of Maternal Immune Activation

“…Specifically, we exposed pregnant mice to poly(I:C), a synthetic mimetic of viral dsRNA analog, a well-documented mouse model of MIA. We and others have reported that poly(I:C)-induced MIA precipitates altered brain and behavioral phenotypes in offspring that mirror abnormalities observed in ASD and related neurodevelopmental conditions such as schizophrenia (Meyer et al, 2006 ; Li et al, 2015 ; Wei et al, 2016 ; Wu et al, 2018 ).…”

A Systematic Review of the Valproic-Acid-Induced Rodent Model of Autism

“…Interestingly, older ages in the VPA groups had decreased social [66] and total [67] exploration than younger VPA-exposed rodents. Older VPA-exposed rodents had a lower discrimination index in the novel object recognition test compared to younger VPA rodents [68]. This difference in discrimination could have played a role in older VPA rodents' social novelty preference impairment.…”

A Developmental Study of Abnormal Behaviors and Altered GABAergic Signaling in the VPA-Treated Rat Model of Autism

“…Although many studies have investigated the role of GABAergic signaling in rodent neural development and behaviors relevant to autism (Tabuchi et al, 2007 ; Cusmano and Mong, 2014 ; Lauber et al, 2016 ; Olexová et al, 2016 ; Wei et al, 2016 ; Chau et al, 2017 ; Watanabe et al, 2017 ), the behavioral ontogeny as determined by changes in GABAergic system of different brain regions is poorly characterized. Here, we employed a VPA rat model of autism to investigate the autism-like behaviors and GABAergic GAD67 expression underlying these altered behaviors in multiple brain areas at the developmental stages from birth to adulthood.…”