Integrative analysis of γδT cells and dietary factors reveals predictive values for autism spectrum disorder in children

Zhang, Lingling; Xu, Yiran; Sun, Shi‐Gang; Chaochao, Liang; Li, Wenhua; Li, Hongwei; Zhang, Xiaoli; Pang, Dizhou; Li, Mengyue; Li, Huihui; Lang, Yongbin; Liu, Jiatian; Jiang, Shuqin; Shi, Xiaoyi; Li, Bingbing; Yang, Yanyan; Wang, Yazhe; Li, Zhenghua; Song, Ci; Duan, Guiqin; Leavenworth, Jianmei W.; Wang, Xiaoyang; Zhu, Changlian

doi:10.1016/j.bbi.2023.03.029

Cited by 3 publications

(1 citation statement)

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“…Notably, Shank3 is a core excitatory postsynaptic protein that regulates synaptic function in multiple brain regions including the medial prefrontal cortex (mPFC), striatum, and hippocampus [ 7 – 9 ]. Shank3 -altered mice and children with autism often have eating disorders [ 3 , 10 , 11 ], and the center of feeding regulation is hypothalamus [ 12 ]. However, the role of the hypothalamus in Shank3 deletion or mutation-caused autism is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Shank3 deficiency elicits autistic-like behaviors by activating p38α in hypothalamic AgRP neurons

Wu,

Wang,

Zhang

et al. 2024

Molecular Autism

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Background SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency. Methods Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3−/−) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α. Results We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3−/− mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3−/− mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. Limitations We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3−/− mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons. Conclusions These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.

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Section: Introductionmentioning

confidence: 99%

Shank3 deficiency elicits autistic-like behaviors by activating p38α in hypothalamic AgRP neurons

Wu,

Wang,

Zhang

et al. 2024

Molecular Autism

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Toward a better understanding of T cell dysregulation in autism: An integrative review

Moreno,

Abu Amara,

Ashwood

2025

Brain, Behavior, and Immunity

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Associations between genetically determined dietary factors and risk of autism spectrum disorder: a Mendelian randomization study

Li,

Liu,

Chen

2024

Front. Nutr.

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BackgroundExisting studies confirm the importance of dietary factors in developing autism spectrum disorder (ASD) and disease progression. Still, these studies are primarily observational, and their causal relationship is unknown. Moreover, due to the extensive diversity of food types, the existing research remains somewhat limited in comprehensiveness. The inconsistency of the results of some studies is very disruptive to the clinic. This study infers a causal relationship between dietary factors on the risk of developing ASD from a genetic perspective, which may lead to significant low-cost benefits for children with ASD once the specificity of dietary factors interfering with ASD is confirmed.MethodsWe performed a two-sample Mendelian randomization (MR) analysis by selecting single nucleotide polymorphisms (SNPs) for 18 common dietary factors from the genome-wide association study (GWAS) database as instrumental variables (IVs) and obtaining pooled data for ASD (Sample size = 46,351) from the iPSYCH-PGC institution. Inverse variance weighted (IVW) was used as the primary analytical method to estimate causality, Cochran's Q test to assess heterogeneity, the Egger-intercept test to test for pleiotropy and sensitivity analysis to verify the reliability of causal association results.ResultsThe MR analysis identified four dietary factors with potential causal relationships: poultry intake (fixed-effects IVW: OR = 0.245, 95% CI: 0.084–0.718, P < 0.05), beef intake (fixed-effects IVW: OR = 0.380, 95% CI: 0.165–0.874, P < 0.05), cheese intake (random-effects IVW: OR = 1.526, 95% CI: 1.003–2.321, P < 0.05), and dried fruit intake (fixed-effects IVW: OR = 2.167, 95% CI: 1.342–3.501, P < 0.05). There was no causal relationship between the remaining 14 dietary factors and ASD (P > 0.05).ConclusionThis study revealed potential causal relationships between poultry intake, beef intake, cheese intake, dried fruit intake, and ASD. Poultry and beef intake were associated with a reduced risk of ASD, while cheese and dried fruit intake were associated with an increased risk. Other dietary factors included in this study were not associated with ASD.

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Integrative analysis of γδT cells and dietary factors reveals predictive values for autism spectrum disorder in children

Cited by 3 publications

References 85 publications

Shank3 deficiency elicits autistic-like behaviors by activating p38α in hypothalamic AgRP neurons

Shank3 deficiency elicits autistic-like behaviors by activating p38α in hypothalamic AgRP neurons

Toward a better understanding of T cell dysregulation in autism: An integrative review

Associations between genetically determined dietary factors and risk of autism spectrum disorder: a Mendelian randomization study

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