Neuroimmune alterations in autism: a translational analysis focusing on the animal model of autism induced by prenatal exposure to valproic acid

Autism Spectrum Disorder (ASD) is a highly prevalent developmental disorder characterized by deficits in communication and social interaction and in stereotyped or repetitive behaviors. Besides the classical behavioral dyad, several comorbidities are frequently present in patients with ASD, such as anxiety, epilepsy, sleep disturbances and gastrointestinal tract dysfunctions. Although the etiology of ASD remains unclear, there is supporting evidence for the involvement of both genetic and environmental factors. Valproic acid (VPA) is an anticonvulsant and mood stabilizer that, when used during the gestational period, increases the risk of ASD in the offspring. The animal model of autism by prenatal exposure to VPA shows construct and face validity, since several changes seen in subjects with autism are also observed in the VPA animal model. Neuroimmune alterations are common both in autistic individuals and in animal models of autism. In addition, exposure to pathogens during the pregnancy is a known risk factor for ASD, and maternal immune activation can lead to autistic-like features in animals. Thus, immunological alterations in pregnancy could affect the developing embryo, since immune molecules can pass through the placental barrier. Here, we summarize important alterations in inflammatory markers, such cytokines and chemokines in patients with ASD and in the VPA animal model

Mood Disorders Induced by Maternal Overnutrition: The Role of the Gut-Brain Axis on the Development of Depression and Anxiety

Since the first evidence suggesting that maternal nutrition can impact the development of diseases in the offspring, much has been elucidated about its effects on the offspring’s nervous system. Animal studies demonstrated that maternal obesity can predispose the offspring to greater chances of metabolic and neurodevelopmental diseases. However, the mechanisms underlying these responses are not well established. In recent years, the role of the gut-brain axis in the development of anxiety and depression in people with obesity has emerged. Studies investigating changes in the maternal microbiota during pregnancy and also in the offspring demonstrate that conditions such as maternal obesity can modulate the microbiota, leading to long-term outcomes in the offspring. Considering that maternal obesity has also been linked to the development of psychiatric conditions (anxiety and depression), the gut-brain axis is a promising target to be further explored in these neuropsychiatric contexts. In the present study, we review the relationship between maternal obesity and anxious and depressive features, exploring the gut-brain axis as a potential mechanism underlying this relationship

Aberrant IL-17 levels in rodent models of Autism Spectrum Disorder:a systematic review

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterised by stereotyped behaviours, specific interests, and impaired communication skills. Elevated levels of pro-inflammatory cytokines, such as interleukin-17A (IL-17A or IL-17), have been implicated as part of immune alterations that may contribute to this outcome. In this context, rodent models have helped elucidate the role of T-cell activation and IL-17 secretion in the pathogenesis of ASD. Regarding the preclinical findings, the data available is contradictory in offspring but not in the pregnant dams, pointing to IL-17 as one of the main drivers of altered behaviour in some models ASD, whilst there are no alterations described in IL-17 levels in others. To address this gap in the literature, a systematic review of altered IL-17 levels in rodent models of ASD was conducted. In total, 28 studies that explored IL-17 levels were included and observed that this cytokine was generally increased among the different models of ASD. The data compiled in this review can help the choice of animal models to study the role of cytokines in the development of ASD, seeking a parallel with immune alterations observed in individuals with this condition. Systematic Review Registration: PROSPERO, identifier CRD42022306558

Abnormal empathy-like pro-social behaviour in the valproic acid model of autism spectrum disorder

Impairments in social behaviour are a defining feature of autism spectrum disorder (ASD). Individuals with ASD also usually present some difficulty to recognise or understand another person's feelings. Therefore, it is possible that altered empathy processing could hinder typical social interaction in ASD. Recently, robust paradigms confirmed that rodents show primordial forms of empathy-like behaviour. Therefore, in this work, we used one of these new protocols to test pro-social behaviour in the rat model of autism induced by Valproic Acid (VPA). We also evaluated possible beneficial effects of Resveratrol, since it can prevent social deficits in the VPA model. Rats were tested on their ability to open a restrainer to release a trapped conspecific. Exposure to VPA precludes the timely manifestation of this empathy-like behaviour, but does not affect its continuation after its first expression. We also found a significant correlation between average speed during the first day of test and becoming an Opener. Similarly, rats able to open the restrainer on the first day had an increased likelihood of repeating this behaviour in the later days of the testing programme. We did not find any protective effects of Resveratrol. Further investigation of empathy-like behaviour in the VPA model and in other models of autism could help to clarify the behavioural and neural processes underpinning the basic aspects of empathy alterations in autistic individuals. [Abstract copyright: Copyright © 2019. Published by Elsevier B.V.

Data on social transmission of food preference in a model of autism induced by valproic acid and translational analysis of circulating microRNA

This article contains data of Social Transmission of Food Preference in an animal model of autism and the evaluation of a set of microRNA analyzed in autistic patients and animal model of autism. The analyses of the absolute consumption of two flavored food by male rats prenatally exposed to valproic acid (VPA) and treated with resveratrol (RSV), showed that VPA animals show a trend to eat less of the flavored food presented by a demonstrator rat. We also identified 13 microRNA with similar levels among rodents' experimental groups, as well as 11 microRNA with no alterations between autistic and control subjects. Further evaluation of mechanisms of VPA and RSV actions on behavioral and molecular alterations can shed light in important biomarkers and etiological triggers of autistic spectrum disorders

Reduced CD4 T Lymphocytes in Lymph Nodes of the Mouse Model of Autism Induced by Valproic Acid

Considering the potential role of lymphocytes in the pathophysiology of autism spectrum disorder (ASD), we aimed to evaluate possible alterations of T cell pools in the lymphoid organs of an animal model of autism induced by valproic acid (VPA). Pregnant Swiss mice received a single intraperitoneal injection of 600 mg/kg of VPA (VPA group) or saline (control group) on day 11 of gestation. Male offspring were euthanized on postnatal day 60 for removal of thy-muses, spleens, and a pool of inguinal, axillary and brachial lymph nodes. Cellularity was evaluated, and flow cytometry analysis was performed on cell suspensions incubated with the mouse antibodies anti-CD3-FITC, anti-CD4-PE, and anti-CD8-PE-Cy7. We observed that the prenatal exposure to VPA induced a reduction in the numbers of CD3+CD4+ T cells in their lymph nodes when compared to the control animals. This was specific since it was not seen in the thymus or spleen. The consistent decrease in the number of CD4+ T cells in subcutaneous lymph nodes of mice from the animal model of autism may be related to the allergic symptoms frequently observed in ASD. Further research is necessary to characterize the immunological patterns in ASD and the connection with the pathophysiology of this disorder. [Abstract copyright: © 2018 S. Karger AG, Basel.

Lactate Protects Microglia and Neurons from Oxygen-Glucose Deprivation/Reoxygenation

Lactate has received attention as a potential therapeutic intervention for brain diseases, particularly those including energy deficit, exacerbated inflammation, and disrupted redox status, such as cerebral ischemia. However, lactate roles in metabolic or signaling pathways in neural cells remain elusive in the hypoxic and ischemic contexts. Here, we tested the effects of lactate on the survival of a microglial (BV-2) and a neuronal (SH-SY5Y) cell lines during oxygen and glucose deprivation (OGD) or OGD followed by reoxygenation (OGD/R). Lactate signaling was studied by using 3,5-DHBA, an exogenous agonist of lactate receptor GPR81. Inhibition of lactate dehydrogenase (LDH) or monocarboxylate transporters (MCT), using oxamate or 4-CIN, respectively, was performed to evaluate the impact of lactate metabolization and transport on cell viability. The OGD lasted 6 h and the reoxygenation lasted 24 h following OGD (OGD/R). Cell viability, extracellular lactate concentrations, microglial intracellular pH and TNF-ɑ release, and neurite elongation were evaluated. Lactate or 3,5-DHBA treatment during OGD increased microglial survival during reoxygenation. Inhibition of lactate metabolism and transport impaired microglial and neuronal viability. OGD led to intracellular acidification in BV-2 cells, and reoxygenation increased the release of TNF-ɑ, which was reverted by lactate and 3,5-DHBA treatment. Our results suggest that lactate plays a dual role in OGD, acting as a metabolic and a signaling molecule in BV-2 and SH-SY5Y cells. Lactate metabolism and transport are vital for cell survival during OGD. Moreover, lactate treatment and GPR81 activation during OGD promote long-term adaptations that potentially protect cells against secondary cell death during reoxygenation

Behavioral alterations in autism model induced by valproic acid and translational analysis of circulating microRNA

Autism spectrum disorder (ASD) is characterized by difficulties in social interaction, communication and language, and restricted repertoire of activities and interests. The etiology of ASD remains unknown and no clinical markers for diagnosis were identified. Environmental factors, including prenatal exposure to valproic acid (VPA), may contribute to increased risk of developing ASD. MicroRNA (miRNA) are small noncoding RNA that regulate gene expression and are frequently linked to biological processes affected in neurodevelopmental disorders. In this work, we analyzed the effects of resveratrol (an antioxidant and anti-inflammatory molecule) on behavioral alterations of the VPA model of autism, as well as the levels of circulating miRNA. We also evaluated the same set of miRNA in autistic patients. Rats of the VPA model of autism showed reduced total reciprocal social interaction, prevented by prenatal treatment with resveratrol (RSV). The levels of miR134-5p and miR138-5p increased in autistic patients. Interestingly, miR134-5p is also upregulated in animals of the VPA model, which is prevented by RSV. In conclusion, our findings revealed important preventive actions of RSV in the VPA model, ranging from behavior to molecular alterations. Further evaluation of preventive mechanisms of RSV can shed light in important biomarkers and etiological triggers of ASD