N-Acetylcysteine Mitigates Social Dysfunction in a Rat Model of Autism Normalizing Glutathione Imbalance and the Altered Expression of Genes Related to Synaptic Function in Specific Brain Areas.

Piergiorgio La Rosa,Sara Schiavi,Fiorella Piemonte,Emilia Carbone,Viviana Trezza,Jessica D'Amico,Sara Petrillo

doi:10.3389/fpsyt.2022.851679

Abstract

Prenatal exposure to valproic acid (VPA) is a risk factor for autism spectrum disorder (ASD) in humans and it induces autistic-like behaviors in rodents. Imbalances between GABAergic and glutamatergic neurotransmission and increased oxidative stress together with altered glutathione (GSH) metabolism have been hypothesized to play a role in both VPA-induced embriotoxicity and in human ASD. N-acetylcysteine (NAC) is an antioxidant precursor of glutathione and a modulator of glutamatergic neurotransmission that has been tested in ASD, although the clinical studies currently available provided controversial results. Here, we explored the effects of repeated NAC (150 mg/kg) administration on core autistic-like features and altered brain GSH metabolism in the VPA (500 mg/kg) rat model of ASD. Furthermore, we measured the mRNA expression of genes encoding for scaffolding and transcription regulation proteins, as well as the subunits of NMDA and AMPA receptors and metabotropic glutamate receptors mGLUR1 and mGLUR5 in brain areas that are relevant to ASD. NAC administration ameliorated the social deficit displayed by VPA-exposed rats in the three-chamber test, but not their stereotypic behavior in the hole board test. Furthermore, NAC normalized the altered GSH levels displayed by these animals in the hippocampus and nucleus accumbens, and it partially rescued the altered expression of post-synaptic terminal network genes found in VPA-exposed rats, such as NR2a, MGLUR5, GLUR1, and GLUR2 in nucleus accumbens, and CAMK2, NR1, and GLUR2 in cerebellum. These data indicate that NAC treatment selectively mitigates the social dysfunction displayed by VPA-exposed rats normalizing GSH imbalance and reestablishing the expression of genes related to synaptic function in a brain region-specific manner. Taken together, these data contribute to clarify the behavioral impact of NAC in ASD and the molecular mechanisms that underlie its effects.

Highlights

Several factors such as gene mutations, gene variations and adverse environmental events concur to the pathogenesis of Autism Spectrum Disorder (ASD)
Post hoc analysis revealed that valproic acid (VPA)-exposed rats spent less time in the stimulus room (∗∗p < 0.01 vs. rats prenatally exposed to SAL, Figure 2A) and sniffing the stimulus animal (∗p < 0.05 vs. rats prenatally exposed to SAL, Figure 2B) compared to SALexposed rats, indicating reduced sociability
Treatment with NAC normalized the deficit displayed by VPA-exposed rats in this test

Summary

Introduction

Several factors such as gene mutations, gene variations and adverse environmental events concur to the pathogenesis of Autism Spectrum Disorder (ASD). When given during gestation, depending on the time window of exposure and the administered dose, VPA is able to cause congenital malformations [3, 4] and to induce core autistic symptoms in the offspring, such as impaired communication, reduced sociability and stereotyped behaviors [5, 6]. Based on this clinical evidence, prenatal exposure to VPA in rodents has been validated as a preclinical model of ASD mimicking one of the environmental factors involved in the pathogenesis of the disease [7–9]. The GABA excitatory-inhibitory shift that normally occurs during delivery is abolished in VPAexposed animals, while restoring this shift rescues their aberrant behavioral phenotype [22]

Methods

Results

Conclusion