Leaky Gut Plays a Critical Role in the Pathophysiology of Autism in Mice by Activating the Lipopolysaccharide-Mediated Toll-Like Receptor 4-Myeloid Differentiation Factor 88-Nuclear Factor Kappa B Signaling Pathway / 神经科学通报·英文版

Increased intestinal barrier permeability, leaky gut, has been reported in patients with autism. However, its contribution to the development of autism has not been determined. We selected dextran sulfate sodium (DSS) to disrupt and metformin to repair the intestinal barrier in BTBR T+tf/J autistic mice to test this hypothesis. DSS treatment resulted in a decreased affinity for social proximity; however, autistic behaviors in mice were improved after the administration of metformin. We found an increased affinity for social proximity/social memory and decreased repetitive and anxiety-related behaviors. The concentration of lipopolysaccharides in blood decreased after the administration of metformin. The expression levels of the key molecules in the toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-nuclear factor kappa B (NF-κB) pathway and their downstream inflammatory cytokines in the cerebral cortex were both repressed. Thus, "leaky gut" could be a trigger for the development of autism via activation of the lipopolysaccharide-mediated TLR4-MyD88-NF-κB pathway.

WDR62-deficiency Causes Autism-like Behaviors Independent of Microcephaly in Mice / 神经科学通报·英文版

Brain size abnormality is correlated with an increased frequency of autism spectrum disorder (ASD) in offspring. Genetic analysis indicates that heterozygous mutations of the WD repeat domain 62 (WDR62) are associated with ASD. However, biological evidence is still lacking. Our study showed that Wdr62 knockout (KO) led to reduced brain size with impaired learning and memory, as well as ASD-like behaviors in mice. Interestingly, Wdr62 Nex-cKO mice (depletion of WDR62 in differentiated neurons) had a largely normal brain size but with aberrant social interactions and repetitive behaviors. WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. Finally, we revealed that retinoic acid gavages significantly alleviated ASD-like behaviors in mice with WDR62 haploinsufficiency, probably by complementing the expression of ASD and synapse-related genes. Our findings provide a new perspective on the relationship between the microcephaly gene WDR62 and ASD etiology that will benefit clinical diagnosis and intervention of ASD.

Inhibiting silence information regulator 2 and glutaminase in the amygdala can improve social behavior in autistic rats / 浙江大学学报·医学版

OBJECTIVE@#To investigate the underlying molecular mechanisms by which silence information regulator (SIRT) 2 and glutaminase (GLS) in the amygdala regulate social behaviors in autistic rats.@*METHODS@#Rat models of autism were established by maternal sodium valproic acid (VPA) exposure in wild-type rats and SIRT2-knockout ( SIRT2 -/-) rats. Glutamate (Glu) content, brain weight, and expression levels of SIRT2, GLS proteins and apoptosis-associated proteins in rat amygdala at different developmental stages were examined, and the social behaviors of VPA rats were assessed by a three-chamber test. Then, lentiviral overexpression or interference vectors of GLS were injected into the amygdala of VPA rats. Brain weight, Glu content and expression level of GLS protein were measured, and the social behaviors assessed.@*RESULTS@#Brain weight, amygdala Glu content and the levels of SIRT2, GLS protein and pro-apoptotic protein caspase-3 in the amygdala were increased in VPA rats, while the level of anti-apoptotic protein Bcl-2 was decreased (all P<0.01). Compared with the wild-type rats, SIRT2 -/- rats displayed decreased expression of SIRT2 and GLS proteins in the amygdala, reduced Glu content, and improved social dysfunction (all P<0.01). Overexpression of GLS increased brain weight and Glu content, and aggravated social dysfunction in VPA rats (all P<0.01). Knockdown of GLS decreased brain weight and Glu content, and improved social dysfunction in VPA rats (all P<0.01).@*CONCLUSIONS@#The glutamate circulatory system in the amygdala of VPA induced autistic rats is abnormal. This is associated with the upregulation of SIRT2 expression and its induced increase of GLS production; knocking out SIRT2 gene or inhibiting the expression of GLS is helpful in maintaining the balanced glutamate cycle and in improving the social behavior disorder of rats.

Oxitocina, vasopresina y conducta social: hipótesis neuropéptida para el trastorno autista / Oxytocin, vasopressin and social behavior: neuropeptide hypothesis

Introducción: El Trastorno Autista es una patología de inicio temprano que evoluciona hacia la cronicidad y se caracteriza principalmente por un desarrollo marcadamente anormal o deficiente de la interacción y comunicación social. Es más frecuente en hombres y si bien se presume que es de origen multifactorial, se plantea que puede ser explicado, al menos en parte, por una alteración en la neurobiología que da sustento a las conductas sociales normales. La Oxitocina y la Vasopresina han sido ampliamente relacionadas con las conductas sociales tanto en animales como en humanos, específicamente han sido relacionadas con las conductas de apego, de filiación y con el Trastorno Autista. Objetivos: Entregar un marco teórico que contribuya a organizar el amplio conocimiento que existe sobre la fisiopatología del Trastorno Autista y que entregue luces tanto para la investigación como para la clínica. Método: Se realiza una revisión bibliográfica sobre el rol que juegan la Oxitocina y la Vasopresina en las conductas sociales sanas y anormales tanto en animales como en humanos centrándose la discusión en la relación que tienen estos neuropéptidos con el Trastorno Autista. Conclusiones: Si bien se presume que la fisiopatología del Trastorno Autista es de origen multifactorial, se logra organizar un marco teórico para la comprensión de la fisiopatología del trastorno desde una hipótesis neuropéptida, lo cual tiene implicancias tanto para la investigación como para la clínica.

Introduction: Autistic disorder is an early onset disease that evolves into chronicity, characterized by the presence of markedly abnormal or deficient development of social interaction and communication. It is more common in men and although presumed to be of multifactorial origin, it is proposed that it can be explained, at least in part, by alterations in the neurobiology which gives supports to normal social behavior. Oxytocin and vasopressin have been widely associated with social behavior in animals and humans, specifically with attachment behaviors, affiliation and Autistic Disorder. Objectives: To provide a theoretical framework in order to help organize the extensive knowledge that exists about the pathophysiology of autistic disorder and to deliver light for both research and clinic. Methods: We performed a systematic review of the role played by oxytocin and vasopressin in healthy and abnormal social behavior in both animals and humans and focused the discussion on the relationship that have these neuropeptides with Autistic Disorder. Conclusions: Understanding the pathophysiology of the Autistic Disorder from a neuropeptide hypothesis, provides a theorethical framework which has implications for both research and clinic.

Espectro autístico: o perfil comunicativo e o desempenho sócio-cognitivo em diferentes situações comunicativas / Austitic spectrum: communicative profile and social-cognitive performance in different communicative situations

As variações nas áreas de linguagem, cognição e interação, nos quadros do espectro autístico, os identificam e ao mesmo tempo são aspectos de diferenciação entre os diagnósticos. O profissional que tem a linguagem como objeto de trabalho e estudo deve se ater a todos os aspectos que podem interferir em seu desenvolvimento, tendo uma ampla visão sobre as áreas alteradas, suas relações e as influências de uma sobre a outra, assim como a intervenção terapêutica. /At the same time that they identify diseases of the autistic spectrum, variations in the language, cognition, and interaction areas are responsible for differences among some diagnosis. The professional that chooses to study language as the subject for his paper and research must be aware of all of the aspects that might interfere in the development...