Autism spectrum disorder (ASD) is characterized by deficits in communication and social interaction, restricted interests, and stereotyped behavior. Environmental factors, such as prenatal exposure to valproic acid (VPA), may contribute to the increased risk of ASD. Since disturbed functioning of the purinergic system has been associated with the onset of ASD and used as a potential therapeutic target for ASD in both clinical and preclinical studies, we analyzed the effects of suramin, a nonselective purinergic antagonist, on behavioral, molecular and immunological in an animal model of autism induced by prenatal exposure to VPA. Treatment with suramin (20 mg/Kg, intraperitoneal) restored sociability in the three-chamber apparatus and decreased anxiety measured by elevated plus maze apparatus, but had no impact on decreased reciprocal social interactions or higher nociceptive threshold in VPA rats. Suramin treatment had no impact on VPA-induced upregulation of P2X4 and P2Y2 in hippocampus, and P2X4 in medial prefrontal cortex, but normalized an increased level of interleukin 6 (IL-6). Our results suggest an important role of purinergic modulation in behavioral, molecular, and immunological aberrations described in VPA model, and suggest that purinergic system might be a potential target for pharmacotherapy in preclinical studies of ASD.

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.

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BackgroundCholinergic and glutamatergic dysfunctions have been widely described in Alzheimer’s disease (AD). However, the role of other neurotransmitter systems, such as the GABAergic, remains poorly understood. In fact, studies evaluating GABAergic neurotransmission in AD patients have provided contradictory results, pointing to a need for a consensus in the literature regarding the GABAergic system in AD. Thus, we aimed at examining whether the GABAergic system is altered in AD.MethodWe systematically reviewed and meta‐analyzed the literature following the PRISMA 2020 guidelines (PROSPERO #alz064082). We searched in the PubMed and Web of Science databases for studies reporting quantitative or semi‐quantitative data of GABA, and GABAergic transporters, receptors, and synthesis enzymes. The participants included were AD subjects and age‐matched cognitively unimpaired (CU) individuals. The effect sizes were determined via the standardized mean difference (SMD) using Hedge’s g method with random effects. The percentage of heterogeneity between studies was estimated using I2 test. Data are presented as SMD [95% CI], I2 %.ResultThe search identified 3,223 papers (Figure 1). Forty‐nine records met the inclusion criteria (a total of 667 AD patients, mean age 75.4, and 584 CU subjects, mean age 72.4). Here, we present results obtained in the CSF, blood, and different brain regions in which more than five studies have been meta‐analyzed. GABA levels were decreased in the CSF (‐0.42 [‐0.74, ‐0.1], p<0.0001, 0%), temporal cortex (‐0.97 [‐1.38, ‐0.55], p<0.0001, 54.6%), occipital cortex (‐1.03 [‐1.86, ‐0.2], p=0.015, 78%), and striatum (‐0.58 [‐1.09, ‐0.07], p=0.025, 0%), but not in the blood (‐0.64 [‐1.39, 0.11], p=0.092, 64.2%), frontal cortex (‐0.49 [‐1.06, 0.08], p=0.09, 73.1%), and hippocampus (‐0.39 [‐0.8, 0.03], p=0.068, 24.7%); GABA A receptor availability was decreased in the frontal (‐0.74 [‐1.44, ‐0.05], p=0.037, 50.5%) and temporal cortices (‐0.73 [‐1.15, ‐0.3], p=0.001, 7.4%), but not in the hippocampus (‐0.79 [‐1.64, 0.06], p=0.068, 66.9%). Figure 2 provides a summary of our findings.ConclusionOur results demonstrated a decrease of GABAergic system components in multiple brain regions and low levels of GABA in the CSF of AD subjects compared to age‐matched CU individuals, pointing to an important role played by GABAergic neurotransmission in the pathophysiology of AD.

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