Sex Differences in Animal Models of Sodium-Valproate-Induced Autism in Postnatal BALB/c Mice: Whole-Brain Histoarchitecture and 5-HT2A Receptor Biomarker Evidence

Abstract

Autism spectrum disorder (ASD) is characterised by problems with social interaction, verbal and nonverbal communication and repetitive behaviour. In mice, the 14th postnatal day is believed to correspond to the third trimester of human embryonic development and is considered a vital period for central nervous system development. It has been shown that ASD affects 2 to 3 times more male than female individuals. In the present study, ASD was induced in 14 postnatal day (PND) BALB/c mice using valproic acid (VPA). VPA administration brought about substantial differences in the histoarchitecture of the brain in both male and female mice, linked to behavioural deficits. We observed that both male and female mice showed similar morphological changes in the prefrontal cortex, hippocampus and Purkinje cells. We also observed hair loss from PND 17 to 25, which was again similar between male and female mice. However, there were higher rates of change in the cerebral cortex, frontal cortex and temporal lobe and hippocampus in VPA-treated male animals. With respect to the cerebellum, we did not observe any alterations by haematoxylin and eosin (H&E) staining, but detailed morphological observation using scanning electron microscopy (SEM) showed a higher rate of phenotype changes in VPA-treated male animals. Moreover, 5-HT2A receptor protein levels were upregulated in the cerebral cortex, hippocampus and Purkinje cells in VPA-treated male mice compared with control animals and VPA-treated female mice, as shown by immunohistochemical analysis. Based on all these findings, we conclude that male animals are more susceptible to VPA-induced ASD than females.

The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior

“…Therefore, studying sex differences in ASD is an interesting issue. In fact, there are more than 80 papers in PubMed on sex influence in different rodent models of ASD (for example, Gouda et al, 2022 ; Ferreira et al, 2022 ; Arnold and Saijo, 2021 ). For this reason, we have performed all our experiments in male, since mixing both sexes surely would arise a high deviation in the data.…”

Sex‐dependent alterations of inflammatory factors, oxidative stress, and histopathology of the brain‐gut axis in a VPA‐induced autistic‐like model of rats

“…In research conducted by Gouda et al, male and female mice displayed comparable morphological alterations in the prefrontal cortex and Purkinje cells. In male, but not female, rodents treated with VPA, they noticed alterations in the cerebral cortex, including the frontal cortex temporal lobe and the hippocampus (Gouda et al, 2022). Male mice treated with VPA had more cerebral cortical changes than female mice, according to a study by Gouda et al This could account for male animals' social and behavioral deficits, which confirms our results (Gouda et al, 2022).…”

“…In male, but not female, rodents treated with VPA, they noticed alterations in the cerebral cortex, including the frontal cortex temporal lobe and the hippocampus (Gouda et al, 2022). Male mice treated with VPA had more cerebral cortical changes than female mice, according to a study by Gouda et al This could account for male animals' social and behavioral deficits, which confirms our results (Gouda et al, 2022). Due to the active roles that the cerebellum and hippocampus play in learning, motor function, anxiety, social functioning, and emotion, all of which are mainly altered in VPA, abnormalities of these brain regions have been recognized as essential in the pathophysiology of autism disorders (Edalatmanesh et al, 2013; Mirza & Sharma, 2019).…”

Maternal separation stress through triggering of the neuro‐immune response in the hippocampus induces autistic‐like behaviors in male mice

“…Immune system‐mediated neuroinflammation lead to defects in synaptogenesis, pruning, cell proliferation, migration, and myelination processes of the nervous system (Reid & Danese, 2020). Clinical and preclinical studies revealed that neuroinflammation is involved in the pathogenesis of ASD (Chan et al, 2020; Gouda et al, 2022).…”