Autism: Molecular Bases, Diagnosis and Therapies

Topic Information

Dear Colleagues,

The causes of autism are still unknown today. More recent studies suggest that autism spectrum disorders may occur following the birth of abnormal neurons (neurobiological causes) that fail to create correct connections with the other nerve cells of the brain, to the point of causing incorrect the functioning of the entire organ. Neuronal networks are formed, above all, during the foetal development phase, allowing one to hypothesize that the cause of this disorder is due to a combination of genetic factors, congenital alterations, and environmental risk factors. There is evidence of familiarity, but also of individuals with autism as carriers of certain genetic diseases (Rett syndrome, Angelman syndrome, etc.), as well as learning disabilities such as dyslexia and dyscalculia, ADHD, Tourette's syndrome, etc. It is therefore necessary to gather more information on the possible causes of the onset of autism in order to better understand it, intervene, and propose targeted therapies. Unfortunately, the diagnosis is often made around the age of 6, when children begin to experience the first difficulties of the condition, with extremely variable symptoms both in extent and in severity. Diagnosis must not be based on psychological tests only, but also on genetic, biochemical and microbiological analysis. A list of possible biomarkers in the urine and blood to allow an early (from the first years of life) and accurate diagnosis is of fundamental importance in order to define the most appropriate therapy. Therapy must be multimodal, i.e., psychological but also pharmacological, especially when some symptoms are particularly debilitating, or present with particular associated pathologies. The outcome of this Special Issue will represent a further step in understanding the molecular mechanisms underlying autism spectrum disorder in order to achieve early diagnosis and provide researchers and clinicians with the most up-to-date information on possible biomarkers to help them understand how to implement therapeutic strategies for patients.

Prof. Dr. Lello Zolla
Prof. Dr. Kunio Yui
Topic Editors

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Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	4.7	3.7	2013	15.4 Days	CHF 2600
Brain Sciences brainsci	3.3	3.9	2011	15.6 Days	CHF 2200
Current Issues in Molecular Biology cimb	3.1	2.4	1999	13.5 Days	CHF 2200
Diagnostics diagnostics	3.6	3.6	2011	20.7 Days	CHF 2600
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900

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14 pages, 3962 KiB  

Open AccessArticle

Inhibition of NKCC1 Ameliorates Anxiety and Autistic Behaviors Induced by Maternal Immune Activation in Mice

by Hai-Long Zhang, Shufen Hu, Shu-Ting Qu, Meng-Dan Lv, Jun-Jun Wang, Xin-Ting Liu, Jia-He Yao, Yi-Yan Ding and Guang-Yin Xu

Curr. Issues Mol. Biol. 2024, 46(3), 1851-1864; https://doi.org/10.3390/cimb46030121 - 28 Feb 2024

Viewed by 559

Abstract

Autism spectrum disorder (ASD) is thought to result from susceptibility genotypes and environmental risk factors. The offspring of women who experience pregnancy infection have an increased risk for autism. Maternal immune activation (MIA) in pregnant animals produces offspring with autistic behaviors, making MIA [...] Read more.

Autism spectrum disorder (ASD) is thought to result from susceptibility genotypes and environmental risk factors. The offspring of women who experience pregnancy infection have an increased risk for autism. Maternal immune activation (MIA) in pregnant animals produces offspring with autistic behaviors, making MIA a useful model for autism. However, how MIA causes autistic behaviors in offspring is not fully understood. Here, we show that NKCC1 is critical for mediating autistic behaviors in MIA offspring. We confirmed that MIA induced by poly(I:C) infection during pregnancy leads to autistic behaviors in offspring. We further demonstrated that MIA offspring showed significant microglia activation, excessive dendritic spines, and narrow postsynaptic density (PSD) in their prefrontal cortex (PFC). Then, we discovered that these abnormalities may be caused by overexpression of NKCC1 in MIA offspring’s PFCs. Finally, we ameliorated the autistic behaviors using PFC microinjection of NKCC1 inhibitor bumetanide (BTN) in MIA offspring. Our findings may shed new light on the pathological mechanisms for autism caused by pregnancy infection. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

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27 pages, 5578 KiB  

Open AccessArticle

Segregated Dynamical Networks for Biological Motion Perception in the Mu and Beta Range Underlie Social Deficits in Autism

by Julia Siemann, Anne Kroeger, Stephan Bender, Muthuraman Muthuraman and Michael Siniatchkin

Diagnostics 2024, 14(4), 408; https://doi.org/10.3390/diagnostics14040408 - 13 Feb 2024

Viewed by 646

Abstract

Objective: Biological motion perception (BMP) correlating with a mirror neuron system (MNS) is attenuated in underage individuals with autism spectrum disorder (ASD). While BMP in typically-developing controls (TDCs) encompasses interconnected MNS structures, ASD data hint at segregated form and motion processing. This coincides [...] Read more.

Objective: Biological motion perception (BMP) correlating with a mirror neuron system (MNS) is attenuated in underage individuals with autism spectrum disorder (ASD). While BMP in typically-developing controls (TDCs) encompasses interconnected MNS structures, ASD data hint at segregated form and motion processing. This coincides with less fewer long-range connections in ASD than TDC. Using BMP and electroencephalography (EEG) in ASD, we characterized directionality and coherence (mu and beta frequencies). Deficient BMP may stem from desynchronization thereof in MNS and may predict social-communicative deficits in ASD. Clinical considerations thus profit from brain–behavior associations. Methods: Point-like walkers elicited BMP using 15 white dots (walker vs. scramble in 21 ASD (mean: 11.3 ± 2.3 years) vs. 23 TDC (mean: 11.9 ± 2.5 years). Dynamic Imaging of Coherent Sources (DICS) characterized the underlying EEG time-frequency causality through time-resolved Partial Directed Coherence (tPDC). Support Vector Machine (SVM) classification validated the group effects (ASD vs. TDC). Results: TDC showed MNS sources and long-distance paths (both feedback and bidirectional); ASD demonstrated distinct from and motion sources, predominantly local feedforward connectivity, and weaker coherence. Brain–behavior correlations point towards dysfunctional networks. SVM successfully classified ASD regarding EEG and performance. Conclusion: ASD participants showed segregated local networks for BMP potentially underlying thwarted complex social interactions. Alternative explanations include selective attention and global–local processing deficits. Significance: This is the first study applying source-based connectivity to reveal segregated BMP networks in ASD regarding structure, cognition, frequencies, and temporal dynamics that may explain socio-communicative aberrancies. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

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15 pages, 3778 KiB  

Open AccessArticle

AST-001 Improves Social Deficits and Restores Dopamine Neuron Activity in a Mouse Model of Autism

by Ki Bum Um, Soyoung Kwak, Sun-Ha Cheon, JuHyun Kim and Su-Kyeong Hwang

Biomedicines 2023, 11(12), 3283; https://doi.org/10.3390/biomedicines11123283 - 12 Dec 2023

Cited by 1 | Viewed by 1042

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social communication and social interaction, restricted and repetitive behavior, and interests. The core symptoms of ASD are associated with deficits in mesocorticolimbic dopamine pathways that project from the ventral tegmental area [...] Read more.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social communication and social interaction, restricted and repetitive behavior, and interests. The core symptoms of ASD are associated with deficits in mesocorticolimbic dopamine pathways that project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). AST-001 is an investigational product currently in a phase 3 clinical trial for treating the core symptoms of ASD, with L-serine as the API (active pharmaceutical ingredient). Because the causes of ASD are extremely heterogeneous, a single genetic ASD model cannot represent all autism models. In this paper, we used the VPA-exposed model, which is more general and widely used than a single genetic model, but this is also one of the animal models of autism. Herein, we conducted experiments to demonstrate the efficacy of AST-001 as L-Serine that alters the regulation of the firing rate in dopamine neurons by inhibiting small conductance Ca²⁺-activated K⁺ channels (SK channels). Through these actions, AST-001 improved sociability and social novelty by rescuing the intrinsic excitabilities of dopamine neurons in VPA-exposed ASD mouse models that showed ASD-related behavioral abnormalities. It is thought that this effect of improving social deficits in VPA-exposed ASD mouse models is due to AST-001 normalizing aberrant SK channel activities that slowed VTA dopamine neuron firing. Overall, these findings suggest that AST-001 may be a potential therapeutic agent for ASD patients, and that its mechanism of action may involve the regulation of dopamine neuron activity and the improvement of social interaction. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

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0 pages, 914 KiB  

Open AccessArticle

Factors in Infancy That May Predict Autism Spectrum Disorder

by Mina Gurevitz and Gerry Leisman

Brain Sci. 2023, 13(10), 1374; https://doi.org/10.3390/brainsci13101374 - 27 Sep 2023

Cited by 1 | Viewed by 1437 | Correction

Abstract

The global increase in the prevalence of ASD (Autism Spectrum Disorder) is of great medical importance, but the reasons for this increase are still unknown. This study sought to identify possible early contributing factors in children who were later diagnosed with ASD. In [...] Read more.

The global increase in the prevalence of ASD (Autism Spectrum Disorder) is of great medical importance, but the reasons for this increase are still unknown. This study sought to identify possible early contributing factors in children who were later diagnosed with ASD. In this retrospective cohort study, postnatal records of 1105 children diagnosed with ASD were analyzed to determine if any signs of ASD could be found in a large database of births and well-baby care programs. We compared the recordings of typically developing children and analyzed the differences statistically. Rapid increases in weight, height, and head circumference during early infancy predict the development of ASD. In addition, low birth weight, older maternal age, and increased weight and height percentiles at six months of age together predict the development of ASD. At two years of age, these four parameters, in addition to impaired motor development, can also predict the development of ASD. These results suggest that the recent increase in ASD prevalence is associated with the “obesity epidemic” and with recommendations of supine sleeping to prevent Sudden Infant Death Syndrome, associated with atypical neural network development in the brain. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

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12 pages, 1849 KiB  

Open AccessArticle

Intraamygdaloid Oxytocin Increases Time Spent on Social Interaction in Valproate-Induced Autism Animal Model

by Dávid Vörös, Orsolya Kiss, Tamás Ollmann, Kitti Mintál, László Péczely, Olga Zagoracz, Erika Kertes, Veronika Kállai, Bettina Réka László, Beáta Berta, Attila Toth, László Lénárd and Kristóf László

Biomedicines 2023, 11(7), 1802; https://doi.org/10.3390/biomedicines11071802 - 23 Jun 2023

Cited by 1 | Viewed by 1244

Abstract

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder that affects about 1.5% of children worldwide. One of the core symptoms is impaired social interaction. Since proper treatment has not been found yet, an investigation of the exact pathophysiology of autism is essential. [...] Read more.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder that affects about 1.5% of children worldwide. One of the core symptoms is impaired social interaction. Since proper treatment has not been found yet, an investigation of the exact pathophysiology of autism is essential. The valproate (VPA)-induced rat model can be an appropriate way to study autism. Oxytocin (OT) may amend some symptoms of ASD since it plays a key role in developing social relationships. In the present study, we investigated the effect of the intraamygdaloid OT on sham and intrauterine VPA-treated rats’ social interaction using Crawley’s social interaction test. Bilateral guide cannulae were implanted above the central nucleus of the amygdala (CeA), and intraamygdaloid microinjections were carried out before the test. Our results show that male Wistar rats prenatally exposed to VPA spent significantly less time on social interaction. Bilateral OT microinjection increased the time spent in the social zone; it also reached the level of sham-control animals. OT receptor antagonist blocked this effect of the OT but in itself did not significantly influence the behavior of the rats. Based on our results, we can establish that intraamygdaloid OT has significantly increased time spent on social interaction in the VPA-induced autism model, and its effect is receptor-specific. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

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20 pages, 3690 KiB  

Open AccessArticle

Investigating the Urinary Metabolome in the First Year of Life and Its Association with Later Diagnosis of Autism Spectrum Disorder or Non-Typical Neurodevelopment in the MARBLES Study

by Jennie Sotelo-Orozco, Rebecca J. Schmidt, Carolyn M. Slupsky and Irva Hertz-Picciotto

Int. J. Mol. Sci. 2023, 24(11), 9454; https://doi.org/10.3390/ijms24119454 - 29 May 2023

Cited by 1 | Viewed by 1554

Abstract

Developmental disabilities are often associated with alterations in metabolism. However, it remains unknown how early these metabolic issues may arise. This study included a subset of children from the Markers of Autism Risks in Babies—Learning Early Signs (MARBLES) prospective cohort study. In this [...] Read more.

Developmental disabilities are often associated with alterations in metabolism. However, it remains unknown how early these metabolic issues may arise. This study included a subset of children from the Markers of Autism Risks in Babies—Learning Early Signs (MARBLES) prospective cohort study. In this analysis, 109 urine samples collected at 3, 6, and/or 12 months of age from 70 children with a family history of ASD who went on to develop autism spectrum disorder (ASD n = 17), non-typical development (Non-TD n = 11), or typical development (TD n = 42) were investigated by nuclear magnetic resonance (NMR) spectroscopy to measure urinary metabolites. Multivariate principal component analysis and a generalized estimating equation were performed with the objective of exploring the associations between urinary metabolite levels in the first year of life and later adverse neurodevelopment. We found that children who were later diagnosed with ASD tended to have decreased urinary dimethylamine, guanidoacetate, hippurate, and serine, while children who were later diagnosed with Non-TD tended to have elevated urinary ethanolamine and hypoxanthine but lower methionine and homovanillate. Children later diagnosed with ASD or Non-TD both tended to have decreased urinary 3-aminoisobutyrate. Our results suggest subtle alterations in one-carbon metabolism, gut-microbial co-metabolism, and neurotransmitter precursors observed in the first year of life may be associated with later adverse neurodevelopment. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

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14 pages, 1764 KiB  

Open AccessArticle

Influence of Auditory Integrative Training on Casein Kinase 2 and Its Impact on Behavioral and Social Interaction in Children with Autism Spectrum Disorder

by Laila Al-Ayadhi, Ramesa Shafi Bhat, Farah Ali Alghamdi, Abdulmalik S. Alhadlaq and Afaf El-Ansary

Curr. Issues Mol. Biol. 2023, 45(5), 4317-4330; https://doi.org/10.3390/cimb45050274 - 15 May 2023

Viewed by 1670

Abstract

Considerable disturbances in post-translational protein phosphorylation have recently been discovered in multiple neurological disorders. Casein kinase-2 (CK2) is a tetrameric Ser/Thr protein kinase that phosphorylates a large number of substrates and contributes in several cellular physiological and pathological processes. CK2 is highly expressed [...] Read more.

Considerable disturbances in post-translational protein phosphorylation have recently been discovered in multiple neurological disorders. Casein kinase-2 (CK2) is a tetrameric Ser/Thr protein kinase that phosphorylates a large number of substrates and contributes in several cellular physiological and pathological processes. CK2 is highly expressed in the mammalian brain and catalyzes the phosphorylation of a large number of substrates that are crucial in neuronal or glial homeostasis and inflammatory signaling processes across synapses. In this study, we investigated the impact of auditory integration therapy (AIT) for the treatment of sensory processing abnormalities in autism on plasma CK2 levels. A total of 25 ASD children, aged between 5 and 12 years, were enrolled and participated in the present research study. AIT was performed for two weeks, for a period of 30 min, twice a day, with a 3 h interval between sessions. Before and after AIT, the Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Short Sensory Profile (SSP) scores were calculated, and plasma CK2 levels were assayed using an ELISA test. The CARS and SRS indices of autism severity improved as a result of AIT, which could be related to the decreased level of plasma CK2. However, the mean value of the SSP scores was not significantly increased after AIT. The relationship between CK2 downregulation and glutamate excitotoxicity, neuro-inflammation, and leaky gut, as etiological mechanisms in ASD, was proposed and discussed. Further research, conducted on a larger scale and with a longer study duration, are required to assess whether the cognitive improvement in ASD children after AIT is related to the downregulation of CK2. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

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11 pages, 273 KiB  

Open AccessArticle

Polymorphisms in Oxytocin and Vasopressin Receptor Genes as a Factor Shaping the Clinical Picture and the Risk of ASD in Males

by Krzysztof M. Wilczyński, Aleksandra Stasik, Lena Cichoń, Aleksandra Auguściak-Duma and Małgorzata Janas-Kozik

Brain Sci. 2023, 13(4), 689; https://doi.org/10.3390/brainsci13040689 - 20 Apr 2023

Viewed by 1167

Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of disorders affecting virtually every population, regardless of their ethnic or socioeconomic background. Their pathogenesis is multifactorial, based on interactions between genetic and environmental factors. The key symptom of ASD are deficits in social communication, [...] Read more.

Autism spectrum disorders (ASD) are a heterogeneous group of disorders affecting virtually every population, regardless of their ethnic or socioeconomic background. Their pathogenesis is multifactorial, based on interactions between genetic and environmental factors. The key symptom of ASD are deficits in social communication, which are the basis of many difficulties in everyday functioning. The aim of the presented study was to analyze the clinical picture of social cognition deficits in boys with autism spectrum disorders and to relate its elements with the frequency of alleles of selected polymorphisms within the oxytocin receptor (OXTR) and vasopressin receptor 1A (AVPR1A) genes. The study included 58 boys with IQ > 90, who were divided into two groups based on a confirmed or excluded ASD diagnosis based on the DSM-5 and ICD-10 criteria and then using the ADOS-2 protocol. The results indicated that polymorphism rs10877969 (T) within the AVPR1a gene was the only one to show a statistically significant association with a higher risk of autism spectrum disorders and has an impact on clinical presentation in the ADOS-2 study, primarily in terms of the social affect subscale. Polymorphisms in the OXTR gene showed no significant association with ASD risk and severity of autistic traits in the ADOS-2 study. In the group of people with ASD and those who are neurotypical, the rs53572 (A) genotype in the OXTR gene significantly increased the severity of the clinical picture of social cognition disorders in reading mind in the eyes test (RMiE) and empathy quotient (EQ) studies. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

12 pages, 7615 KiB  

Open AccessArticle

EEG Features in Autism Spectrum Disorder: A Retrospective Analysis in a Cohort of Preschool Children

by Marta Elena Santarone, Stefania Zambrano, Nicoletta Zanotta, Elisa Mani, Sara Minghetti, Marco Pozzi, Laura Villa, Massimo Molteni and Claudio Zucca

Brain Sci. 2023, 13(2), 345; https://doi.org/10.3390/brainsci13020345 - 17 Feb 2023

Cited by 4 | Viewed by 3262

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that can be associated with intellectual disability (ID) and epilepsy (E). The etiology and the pathogenesis of this disorder is in most cases still to be clarified. Several studies have underlined that the EEG [...] Read more.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that can be associated with intellectual disability (ID) and epilepsy (E). The etiology and the pathogenesis of this disorder is in most cases still to be clarified. Several studies have underlined that the EEG recordings in children with these clinical pictures are abnormal, however the precise frequency of these abnormalities and their relationship with the pathogenic mechanisms and in particular with epileptic seizures are still unknown. We retrospectively reviewed 292 routine polysomnographic EEG tracings of preschool children (age < 6 years) who had received a first multidisciplinary diagnosis of ASD according to DSM-5 clinical criteria. Children (mean age: 34.6 months) were diagnosed at IRCCS E. Medea (Bosisio Parini, Italy). We evaluated: the background activity during wakefulness and sleep, the presence and the characteristics (focal or diffuse) of the slow-waves abnormalities and the interictal epileptiform discharges. In 78.0% of cases the EEG recordings were found to be abnormal, particularly during sleep. Paroxysmal slowing and epileptiform abnormalities were found in the 28.4% of the subjects, confirming the high percentage of abnormal polysomnographic EEG recordings in children with ASD. These alterations seem to be more correlated with the characteristics of the underlying pathology than with intellectual disability and epilepsy. In particular, we underline the possible significance of the prevalence of EEG abnormalities during sleep. Moreover, we analyzed the possibility that EEG data reduces the ASD clinical heterogeneity and suggests the exams to be carried out to clarify the etiology of the disorder. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

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17 pages, 40206 KiB  

Open AccessArticle

Possible Mechanisms of the Neuroprotective Actions of Date Palm Fruits Aqueous Extracts against Valproic Acid-Induced Autism in Rats

by Abdelaziz M. Hussein, Seham Ahmed Mahmoud, Khalid Mohammed Elazab, Ahmed F. Abouelnaga, Marwa Abass, Ahmed A. H. Mosa, Mennatullah A. M. Hussein and Mohamed E. G. Elsayed

Curr. Issues Mol. Biol. 2023, 45(2), 1627-1643; https://doi.org/10.3390/cimb45020105 - 14 Feb 2023

Cited by 1 | Viewed by 1915

Abstract

The current study aimed to determine how palm date aqueous fruit extracts (AFE) affected the autistic-like behaviors brought on by valproic acid (VPA) injection, as well as any potential contributions from Sirt-1, oxidative stress, apoptosis, and autophagy. The pregnant Sprague Dawley females were [...] Read more.

The current study aimed to determine how palm date aqueous fruit extracts (AFE) affected the autistic-like behaviors brought on by valproic acid (VPA) injection, as well as any potential contributions from Sirt-1, oxidative stress, apoptosis, and autophagy. The pregnant Sprague Dawley females were treated with VPA at 12.5th gestation day and pregnant females and their offspring were treated with AFE orally at doses of 4 mg/Kg by gastric gavage for 45 days after birth. The elevated plus-T maze, water maze, and rotarod tests were used to examine autism-like behaviors. At the end of the study, the expression of Nrf2, heme oxygenase (HO-1), Sirt-1, caspase-3 (a marker of apoptosis), LC3 (a marker of autophagy), and NFκB (inflammatory cytokines) were evaluated along with the oxidative stress in brain tissues and the histological changes in the cerebellum and hippocampus. The neurobehavioral assessments significantly declined due to VPA, which also significantly increased oxidative stress in the brain tissues and significantly decreased Nrf2 and HO-1 expression. Additionally, VPA administration caused significant increase in the expression of caspase-3 in the cerebellar cortex, not in the hippocampus; LC3 and NFκB in the hippocampus, not in the cerebellar cortex; and significant reduction in the expression of Sirt-1 in the hippocampus, not in the cerebellum. On the other hand, AFE treatment significantly improved the neurobehavioral changes as well as it improved significantly the oxidative stress and the expression of LC3, NFκB, NrF2, HO-1, and Sirt-1 in the cerebellum and hippocampus. Conclusions: AFE administration might improve the autistic-like symptoms induced by VPA in rats via attenuation of the oxidative stress, upregulation of Nrf2 and HO-1, Sirt-1 and LC3 expression with downregulation of caspase-3, and NFκB expression in the cerebellum and hippocampus. Full article

(This article belongs to the Topic Autism: Molecular Bases, Diagnosis and Therapies)

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