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

Abstract

Although studies have investigated the role of gamma-aminobutyric acid (GABA)ergic signaling in rodent neural development and behaviors relevant to autism, behavioral ontogeny, as underlain by the changes in GABAergic system, is poorly characterized in different brain regions. Here, we employed a valproic acid (VPA) rat model of autism to investigate the autism-like behaviors and GABAergic glutamic acid decarboxylase 67 (GAD67) expression underlying these altered behaviors in multiple brain areas at different developmental stages from birth to adulthood. We found that VPA-treated rats exhibited behavioral abnormalities relevant to autism, including delayed nervous reflex development, altered motor coordination, delayed sensory development, autistic-like and anxiety behaviors and impaired spatial learning and memory. We also found that VPA rats had the decreased expression of GAD67 in the hippocampus (HC) and cerebellum from childhood to adulthood, while decreased GAD67 expression of the temporal cortex (TC) was only observed in adulthood. Conversely, GAD67 expression was increased in the prefrontal cortex (PFC) from adolescence to adulthood. The dysregulated GAD67 expression could alter the excitatory-inhibitory balance in the cerebral cortex, HC and cerebellum. Our findings indicate an impaired GABAergic system could be a major etiological factor occurring in the cerebral cortex, HC and cerebellum of human cases of autism, which suggests enhancement of GABA signaling would be a promising therapeutic target for its treatment.

Gender Related Changes in Gene Expression Induced by Valproic Acid in A Mouse Model of Autism and the Correction by S-adenosyl Methionine. Does It Explain the Gender Differences in Autistic Like Behavior?

“…VPA is a strong HDAC inhibitor, playing an important role in transcriptional regulation; thus it is reasonable to assume that gene expression changes detected in the prefrontal cortex of 60 day old adult mice results from VPA induced epigenetic modifications accumulating during early postnatal developmental stages in the brain. Indeed VPA –induced changes in gene expression were reported by several investigators [31,32,33].…”

“…Nevertheless, specific cellular abnormalities that link genes with behavior remain obscure. Most studies exploring gene alternation in VPA exposed rodents focused on specific set of genes or genes involved in the process of interest [31,32,33]. Only a few studies demonstrated comprehensive genetic analysis.…”

Hippocampal neurons isolated from rats subjected to the valproic acid model mimic in vivo synaptic pattern: evidence of neuronal priming during early development in autism spectrum disorders

“…Alterations in synapse markers have been previously described in the hippocampus of VPA animals at postnatal ages concomitant with exploratory and social deficits [ 38 , 72 , 73 ]. In fact, the structural synaptic marker synaptophysin (SYN) is reduced in the CA3 hippocampal region of VPA animals in the juvenile period [ 38 ].…”

Oxytocin Differentiated Effects According to the Administration Route in a Prenatal Valproic Acid-Induced Rat Model of Autism

“…A recent meta-analysis has demonstrated that large impairments in both phonological and spatial-visual domains of working memory are a characteristic of individuals with ASD independent of their IQ [1]. Spatial memory impairment has been studied previously in VPA rodent autistic models, mostly using the Morris water maze [68][69][70] or radial arm maze [71], and with some exception [72], learning and memory impairment for VPA models were highlighted. Our results are in line with these and also confirm a recent study using Korean ginseng to reverse autistic deficits in a VPA rat model that exhibited altered short-term memory [73].…”