Resveratrol Prevents Cytoarchitectural and Interneuronal Alterations in the Valproic Acid Rat Model of Autism

Abstract

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by several alterations, including disorganized brain cytoarchitecture and excitatory/inhibitory (E/I) imbalance. We aimed to analyze aspects associated with the inhibitory components in ASD, using bioinformatics to develop notions about embryonic life and tissue analysis for postnatal life. We analyzed microarray and RNAseq datasets of embryos from different ASD models, demonstrating that regions involved in neuronal development are affected. We evaluated the effect of prenatal treatment with resveratrol (RSV) on the neuronal organization and quantity of parvalbumin-positive (PV+), somatostatin-positive (SOM+), and calbindin-positive (CB+) GABAergic interneurons, besides the levels of synaptic proteins and GABA receptors in the medial prefrontal cortex (mPFC) and hippocampus (HC) of the ASD model induced by valproic acid (VPA). VPA increased the total number of neurons in the mPFC, while it reduced the number of SOM+ neurons, as well as the proportion of SOM+, PV+, and CB+ neurons (subregion-specific manner), with preventive effects of RSV. In summary, metabolic alterations or gene expression impairments could be induced by VPA, leading to extensive damage in the late developmental stages. By contrast, due to its antioxidant, neuroprotective, and opposite action on histone properties, RSV may avoid damages induced by VPA.

GABAergic synaptic transmission and cortical oscillation patterns in the primary somatosensory area of a valproic acid rat model of autism spectrum disorder

“…It is possible to consider that VPA might be affecting the migration process of this interneuron subpopulation, and further studies must elucidate whether LHX6 could play important roles in the migration of GABAergic interneurons during embryogenesis and in their proper placement during the postnatal life of the VPA animal model of ASD. There are current evidences demonstrating that LHX6 remain expressed as the cortex matures (Cobos et al, 2005) and proinflammatory stimuli during gestational period (inducing a maternal immune activation alters gene expression associated with migration, function and placement of interneurons (Bergdolt & Dunaevsky, 2019; Oskvig et al, 2012; Santos‐Terra et al, 2022). Besides, interneurons, such as PV‐expressing cells, start the migration from MGE around embryonic day (ED) 12.5 in rodents, a proximal period during which the VPA injection is administered in the VPA rodent model of ASD (Kelsom & Lu, 2013).…”

“…We considered the statistical power of 80%, the effect size (0.85 for in vivo electrophysiology and 0.8 for in vitro electrophysiology) and α = 0.05 (two‐tailed). The effect size was based on previous in vivo and in vitro experiments of our group (Pasquetti et al, 2019) and previous studies showing the effect of RSV‐ and VPA‐treated rats (Bambini‐Junior et al, 2014; Deckmann et al, 2021; Fontes‐Dutra et al, 2018; Hirsch et al, 2018; Santos‐Terra et al, 2022; Santos‐Terra, Deckmann, Schwingel, et al, 2021), where smaller sample sizes were used to find a significant difference between groups. Parametric data from in vitro electrophysiology were analysed by two‐way ANOVA followed by the Tukey post hoc test.…”

“…Strikingly, resveratrol (trans-3,5,4 0 -trihydroxystilbene, RSV), a polyphenol with anti-inflammatory and antioxidant properties, is capable of modulating cytokines, chemokines and JAK/STAT pathways (de S a Coutinho et al, 2018), as well as SIRT enzymes, which also contribute to its anti-inflammatory effects (Kalliora et al, 2019). Previous work from our group showed that RSV was capable of preventing many VPA-induced alterations from behavioural to molecular level (Bambini-Junior et al, 2014;Fontes-Dutra et al, 2018;Santos-Terra et al, 2022;. When administered in pregnant rats of the VPA animal model of ASD, RSV was able to prevent not only the cortical displacement of PV + interneurons in PSSA (Fontes-Dutra et al, 2018) but also of PV + , SST + and CB + GABAergic interneurons in the medial prefrontal cortex (mPFC) of the offspring (Santos-Terra et al, 2022), highlighting its neuroprotective role in early stages of neurodevelopment.…”

“…Previous work from our group showed that RSV was capable of preventing many VPA‐induced alterations from behavioural to molecular level (Bambini‐Junior et al, 2014; Deckmann et al, 2021; Fontes‐Dutra et al, 2018; Santos‐Terra et al, 2022; Santos‐Terra, Deckmann, Schwingel, et al, 2021). When administered in pregnant rats of the VPA animal model of ASD, RSV was able to prevent not only the cortical displacement of PV + interneurons in PSSA (Fontes‐Dutra et al, 2018) but also of PV + , SST + and CB + GABAergic interneurons in the medial prefrontal cortex (mPFC) of the offspring (Santos‐Terra et al, 2022), highlighting its neuroprotective role in early stages of neurodevelopment.…”

Altered expression of glycan patterns and glycan-related genes in the medial prefrontal cortex of the valproic acid rat model of autism

“…Therefore, disturbances in the expression of ECM components could lead to altered signaling, disturbing proper cellular functioning, and, in the case of neurons, abnormal outgrowth and synaptic functioning ( Irie et al, 2012 ; Mutalik and Gupton, 2021 ). In the VPA animal model, neurons of the mPFC displayed cytoarchitectural alterations ( Mansour et al, 2019 ), excitatory/inhibitory imbalance ( Santos-Terra et al, 2022 ) and altered synaptic plasticity ( Rinaldi et al, 2008 ). Taken together, we found the aberrant expression of glycan patterns and glycan-related genes in the prenatal VPA exposure model of autism.…”