Impairment in social interaction and hippocampal long-term potentiation at perforant pathway-dentate gyrus synapses in a prenatal valproic acid-induced rat model of autism

Abstract

It is well established that prenatal valproic acid exposure in rats leads to autism-like behaviors and social deficits. Long-term potentiation changes in the brain have been proposed as a potential mechanism in the development of autistic behaviour. However, there are controversies regarding the effect of in utero valproic acid exposure on long-term potentiation. This study examined the social interaction, and long-term potentiation induction in perforant pathway-dentate gyrus synapses in male offspring of a rat model of autism induced by prenatal exposure to valproic acid. On embryonic day 12.5, the pregnant dams received an injection of 500 mg/kg valproic acid (intraperitoneal) to produce the autism model. The sociability test was performed between postnatal days 37 and 40. The offsprings were urethane-anesthetized and placed into a stereotaxic apparatus for surgery, electrode implantation, and field potential recording on postnatal days 45 to 55. In the dentate gyrus region, excitatory post synaptic potentials slope and population spike amplitude were measured. valproic acid-exposed offspring showed significantly impaired social interaction. The Birth weight in valproic acid-exposed rats was significantly lower than control rats. The dentate gyrus synapses’ ability to induce long-term potentiation was hampered by valproic acid exposure. The decreasing excitatory post synaptic potential slope and population spike amplitude of long-term potentiation provide evidence in favor of this notion. It is widely supposed that the hippocampus plays a central role in the process of learning and memory as well as social interaction and social memory. Therefore, deficiencies in hippocampal synaptic plasticity may be responsible, at least in part, for the social interaction deficits in valproic acid -exposed rats.

Gestational hypothyroxinemia induces ASD-like phenotypes in behavior, proinflammatory markers, and glutamatergic protein expression in mouse offspring of both sexes

“…Notably, the HTX-offspring, regardless of sex, showed extended interaction with the first social stimulus compared to the new one ( Figure 5 , Supplementary Tables 1-1.4a-l ). These trends were concordant with previous observations in different ASD-like models, including MIA and VPA offspring, where males tend to manifest more pronounced deficits in social interaction abilities ( 82 , 83 ). In the context of the three-chamber test, these results are indicators of impaired social skills, which are widely recognized to correlate with recurring ASD-like behaviors in both humans and mice ( 84 – 86 ).…”

Sex and age differences in social and cognitive function in offspring exposed to late gestational hypoxia

“…we observed no gestational CIH-associated changes in proteins associated with glutamatergic, dopaminergic, and serotonergic functions, regardless of sex or age of the offspring. We also examined markers for cellular activity (EGR-1) and neurogenesis (doublecortin) within the dentate gyrus region of the dorsal hippocampus, as cellular activity and neurogenesis within the dentate gyrus is important in mediating spatial memory [120,121] and social function [67-70], as well as being associated with ASD [122,123]. We found no effects of late gestational CIH on EGR-1 or doublecortin protein expression in the dentate gyrus, regardless of sex or age.…”

“…We found no effects of late gestational CIH on EGR-1 or doublecortin protein expression in the dentate gyrus, regardless of sex or age. Future studies need to be conducted to examine the electrophysiological properties (long-term potentiation and long-term depression) of dorsal hippocampal neurons and neurogenesis (bromodeoxyuridine, BrdU), as dysfunction in these cellular properties have been linked with ASD [122,123].…”

Sex-Related Changes in the Clinical, Genetic, Electrophysiological, Connectivity, and Molecular Presentations of ASD: A Comparison between Human and Animal Models of ASD with Reference to Our Data

“…Even fewer studies have looked at possible differences in gene expression or brain structure/function between male and female rodents with ASD-like behavior. Some researchers have used only males, to eliminate possible sex differences [ 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 ] in behaviors, such as anxiety-related behaviors and repetitive behaviors [ 139 , 140 ]. Kataoka et al [ 140 ] found that prenatal VPA in mice induced transient histone hyper-acetylation in the brains of offspring of male and female mice.…”