MOLECULAR PSYCHIATRY
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2025
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IF 10.1
Qin Qian,Li Mengyue,Fan Linlin,Zeng Xin,Zheng Danyang,Wang Han,Jiang Yutong,Ma Xinrui,Xing Lei,Wu Lijie,Liang Shuang
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder. The microglia activation is a hallmark of ASD, which involves increased glycolysis. Elevated glycolysis regardless of oxygen availability, known as “Warburg effect”, is crucial to pathogenesis in neuropsychiatric disorders. Psychiatric risk gene MIR137 plays an important role in neurogenesis and neuronal maturation, but the impact on neuroinflammation and glucose metabolism remains obscure. Extracellular vesicles (EVs) can delivery miR-137 crossing the blood-brain barrier. Meanwhile, EVs can help miR-137 avoid being rapidly degraded by endogenous nucleases. Here, after first detecting miR-137 decreased both in the peripheral blood of individuals with ASD and the serum and cerebellum of BTBR mice, we demonstrated that microglia activation, the level of lactate and key enzymes (HK2, PKM2 and LDHA) involved in glycolysis were increased significantly in BTBR mice. Of particular note, EVs engineered by rabies virus glycoprotein (RVG) could promote the miR-137 (RVG-miR137-EVs) targeted to the brain accurately, and alleviated autism-like behaviors. Pro-inflammatory activation of BTBR mice was considerably inhibited by RVG-miR137-EVs via tail vein administration, accompanied by decreased lactate production. Mechanically, these effects were attributed to TLR4 , the key target gene, which was regulated by miR-137. The TLR4/NF-κB pathway was inhibited, subsequently reducing HIF-1α and repressing the transcription of HK2, PKM2 and LDHA involved in glycolysis. Pharmacological inhibition of glycolysis and TLR4 attenuated microglial activation and lactate production, ultimately improved autism-like behaviors of BTBR mice. In conclusion, our results indicated that miR-137 could alleviate autism-like behaviors by HIF-1α-mediated adaptive metabolic changes in glycolysis and neuroinflammation.
研究领域:
神经科学
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分子生物学
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医学
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DOI
PubMed
高影响因子
Metabolites
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2025
·Vol. 15
·期 2
·134
·
IF 3.7
Yunchen Meng,Yiling Hu,Yaqi Xue,Zhiping Zhen
Objectives:This study aimed to investigate the regulatory impact of early swimming intervention on striatal metabolism inShank3gene knockout ASD model rats.Methods:Shank3gene knockout exon 11–21 male 8-day-old SD rats were used as experimental subjects and randomly divided into the following three groups: aShank3knockout control group (KC), a wild-type control group (WC) from the same litter, and aShank3knockout swimming group (KS). The rats in the exercise group received early swimming intervention for 8 weeks starting at 8 days old. LC-MS metabolism was employed to detect the changes in metabolites in the striatum.Results:There were 17 differential metabolites (14 down-regulated) between the KC and WC groups, 19 differential metabolites (18 up-regulated) between the KS and KC groups, and 22 differential metabolites (18 up-regulated) between the KS and WC groups.Conclusions:The metabolism of striatum inShank3knockout ASD model rats is disrupted, involving metabolites related to synaptic morphology, and the Glu and GABAergic synapses are abnormal. Early swimming intervention regulated the striatal metabolome group of the ASD model rats, with differential metabolites primarily related to nerve development, synaptic membrane structure, and synaptic signal transduction.
研究领域:
神经科学
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代谢组学
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行为学
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DOI
PubMed
高影响因子
CELL RESEARCH
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2017
·Vol. 28
·期 1
·48-68
·
IF 15.606
Xu Xingxing,Li Chuanyin,Gao Xiaobo,Xia Kun,Guo Hui,Li Yali,Hao Zijian,Zhang Lei,Gao Daming,Xu Chenfan,Xu Huatai,Xiong Zhi-Qi,Qiu Zilong,Mei Ling,Xie Xiaoduo,Ruan Kangcheng,Hu Ronggui
The autism spectrum disorders (ASDs) are a collection of human neurological disorders with heterogeneous etiologies. Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. Excessive UBE3A dosage was found to impair RA-mediated neuronal homeostatic synaptic plasticity. ASD-like symptoms were recapitulated in mice by overexpressing UBE3A in the prefrontal cortex or by administration of an ALDH1A antagonist, whereas RA supplements significantly alleviated excessive UBE3A dosage-induced ASD-like phenotypes. By identifying reduced RA signaling as an underlying mechanism in ASD phenotypes linked to UBE3A hyperactivities, our findings introduce a new vista of ASD etiology and facilitate a mode of therapeutic development against this increasingly prevalent disease.
研究领域:
神经科学
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分子生物学
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遗传学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Yuanyuan Song,Xing Zhang,Binquan Wang,Xiaoxiao Luo,Ke Zhang,Xiaoyan Zhang,Qian Wu,Mingkuan Sun
Bisphenol AP (BPAP), an environmental endocrine disruptor, may cause neurodevelopmental disorders affecting human health. Studies have shown that BPAP impacts hormone synthesis and metabolism, causes social behavior abnormalities, and induces anxiety-like behavioral impairments in mice. However, evidence for the neurobehavioral effects of BPAP is still lacking. Here, we examined the toxic effects of BPAP on neurodevelopment using a Drosophila model. We assessed the role of BPAP exposure in autism-like behavior and explored the underlying mechanisms. Our findings indicated that BPAP exposure reduced pupation and eclosion rates and delayed growth in Drosophila . Furthermore, BPAP exposure caused autism-like behaviors, characterized by increased grooming times and aberrant social interactions, along with abnormalities in locomotor activity, as well as learning and memory ability. Mechanistically, we found that BPAP decreases the number of neuroblasts (NBs) and mature intermediate neural progenitors (INPs) in the 3rd larval brain, impairing axon guidance in the mushroom body of the adult Drosophila brain. Additionally, our transcriptome analysis revealed that BPAP exposure alters the expression of neurodevelopment-related genes ( Nplp3 , sand , lush , and orco ) and affects the estrogen signaling pathway ( Hsp70Ab , Hsp70Bc , Hsp70Ba , and Hsp70Bb ). These changes potentially explain the BPAP-induced autism-like behavior in Drosophila .
研究领域:
神经生物学
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环境科学
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分子生物学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
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2024
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IF 10.7
Wentian Li,Qingmin Kong,Min Guo,Linlin Wang,Peijun Tian,Jingyu Lu,Jianxin Zhao,Wei Chen,Gang Wang
This study was conducted to elucidate the effects of different degrees of substitution (DS) on the properties of propionylated and butyrylated starches and to investigate their efficacy and mechanisms in ameliorating autism-like phenotypes. Fourier transform infrared spectra of propionylated and butyrylated starches revealed the presence of the C O absorption peak at 1730 cm −1 . Additionally, as the DS increased, the surface of the starch granules became rougher, and the crystallinity decreased. Moreover, in vitro digestion tests demonstrated that propionylated and butyrylated starches with a DS of approximately 0.25 exhibited enhanced resistance to digestion. Animal experiments indicated that butyrylated starch significantly improved abnormal behaviors in autism-like rats and increased butyrate accumulation in the colon. Furthermore, butyrylated starch normalized aberrant expression of G protein-coupled receptor 41 and tryptophan hydroxylase 1 in the colon, promoting 5-hydroxytryptamine metabolism and suppressing the expression of ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein in the gut and brain. These findings demonstrate that butyrylated starch effectively alleviates autism-like phenotypes in rats, supporting strategies to mitigate autism and develop new applications for natural corn starch.
研究领域:
营养学
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神经科学
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生物化学
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产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF PATHOLOGY
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2024
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IF 4.7
Xiaojuan Lu,Yixing Song,Jiaqi Wang,Yunyun Cai,Siwan Peng,Jiaqi Lin,Biqin Lai,Junjie Sun,Tianqing Liu,Gang Chen,Lingyan Xing
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with a complex etiology. Recent evidence suggests that dopamine plays a crucial role in neural development. However, whether and how disrupted dopaminergic signaling during development contributes to ASD remains unknown. In this study, human brain RNA sequencing transcriptome analysis revealed a significant correlation between changes in dopaminergic signaling pathways and neural developmental signaling in ASD patients. In the zebrafish model, disrupted developmental dopaminergic signaling led to neural circuit abnormalities and behavior reminiscent of autism. Dopaminergic signaling may impact neuronal specification by potentially modulating integrins. These findings shed light on the mechanisms underlying the link between disrupted developmental dopamine signaling and ASD, and they point to the possibility of targeting dopaminergic signaling in early development for ASD treatment.
研究领域:
神经科学
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发育生物学
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医学遗传学
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DOI
高影响因子
BEHAVIOURAL NEUROLOGY
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2023
·
IF 2.8
Lijuan Chen,Jing Li,Xinglian Liu,Zhiwei Zhao,Yan Jin,Yikun Fu,Aiqin Zhou,Chengqun Wang,Yan Zhou
Vitamin B6 (VB6) exhibits therapeutic effects towards autism spectrum disorder (ASD), but its specific mechanism is poorly understood. Rat dams were treated with VB6 standard, VB6 deficiency, or VB6 supplementary diet, and the same treatment was provided to their offspring, with their body weights monitored. Three-chambered social test and open field test were employed to evaluate the effect of VB6 on autism-like behaviors. Gamma-aminobutyric acid (GABA) generation and synaptic inhibition of neurons in the hippocampus of rat were detected via immunofluorescence staining, followed by the measurement of GABA concentration through high-performance liquid chromatography (HPLC). The role of VB6 in the autophagy and apoptosis of cells was determined via Western blot and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). In order to conduct rescue experiments, the inhibition of mammalian target of rapamycin (mTOR) or the activation of GABA was achieved by drug administration to the offspring rats with VB6 deficiency. As a result, no evident difference in weight was observed in the offspring with varied VB6 treatments. VB6 deficiency impaired social interaction; aggravated self-grooming and bowel frequency; decreased GABA concentration, VIAAT, GAD67, vGAT expressions, and LC3 II/LC3 I ratio; increased p62 level and p-mTOR/mTOR ratio; and promoted cell apoptosis. Inhibition of mTOR reversed the effect of VB6 deficiency on cell autophagy. GABA activation or mTOR inhibition offset the role of VB6 deficiency in autism-like behaviors and hippocampal GABA expression. Collectively, VB6 deficiency induces autism-like behaviors in rats by regulating mTOR-mediated autophagy in the hippocampus.
研究领域:
神经科学
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药理学
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行为科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Nanoscale
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2025
·
IF 5.1
Minghui Li,Song Wang,Lingling Chang,Ruiting Chen,Yuhang Liu,Zhengjie Ye,Yuhang Zhao,YiFan Ma,Jing Yang,Xinyu Gan,Yongzhi Zhuang,Peng Wang
Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of uncertain etiology. Current studies suggest that ASD progression is closely linked to an imbalance between oxidative stress and antioxidant capacity, marked by elevated levels of reactive oxygen species (ROS) and reduced concentrations of antioxidant molecules such as superoxide dismutase (SOD) and glutathione (GSH). Although the human body does possess endogenous ROS-scavenging enzymes, their sensitivity to environmental conditions and the difficulties of large-scale production limit their practical application. Consequently, substantial efforts have been dedicated in recent years to developing artificial enzymes with ROS-scavenging activity. Among these, ROS-scavenging nanozymes have been widely used due to their enhanced stability and multifunctionality. Notably, only a few manganese-containing nanozymes have been reported to exhibit effective reactive oxygen species (ROS) scavenging activity thus far. Methods: In this study, we utilized Mn3O4 nanozymes (Mn3O4 NZs) exhibiting superoxide dismutase, catalase, and hydroxyl radical–scavenging activities. We assessed brain injury, as well as the antioxidative and anti-inflammatory effects of Mn3O4 NZs through behavioral tests, Nissl staining, immunofluorescence assays, and a laser speckle imaging system. Furthermore, we explored the underlying mechanisms of Mn3O4 NZs by employing ELISA kits, oxidative stress detection kits, and immunofluorescence analysis. Results: The results demonstrated that Mn3O4 NZs increase cerebral blood flow and effectively ameliorate ischemic and hypoxic conditions in BTBR mice. Moreover, they improve social deficits, repetitive stereotyped behaviors, cognitive impairment, and neuronal morphological damage. Further in vitro experiments confirmed that Mn3O4 NZs exert neuroprotective effects in BTBR mice by mitigating oxidative stress and inflammation. Conclusion: These findings indicate that Mn3O4 NZs exhibit excellent antioxidant and anti-inflammatory effects in vitro and effectively enhance cerebral blood flow, ameliorate behavioral deficits, and alleviate neuronal damage in BTBR mice in vivo. Collectively, our results suggest that Mn3O4 NZs exert neuroprotective effects in the hippocampus of BTBR mice by reducing oxidative stress, mitigating neuroinflammation, and rescuing neuronal injury. Consequently, they hold promise as a potential nanomaterial for the treatment of autism.
研究领域:
神经科学
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纳米医学
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药理学
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分子生物学
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行为科学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Genetics
·
2022
·
IF 4.772
Liqin Yang,Zhixiong Xia,Jianhua Feng,Menghuan Zhang,Pu Miao,Yingjie Nie,Xiangyan Zhang,Zijian Hao,Ronggui Hu
Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder with the underlying etiology yet incompletely understood and no cure treatment. Patients of fragile X syndrome (FXS) also manifest symptoms, e.g. deficits in social behaviors, that are core traits with ASD. Several studies demonstrated that a mutual defect in retinoic acid (RA) signaling was observed in FXS and ASD. However, it is still unknown whether RA replenishment could pose a positive effect on autistic-like behaviors in FXS. Herein, we found that RA signaling was indeed down-regulated when the expression of FMR1 was impaired in SH-SY5Y cells. Furthermore, RA supplementation rescued the atypical social novelty behavior, but failed to alleviate the defects in sociability behavior or hyperactivity, in Fmr1 knock-out (KO) mouse model. The repetitive behavior and motor coordination appeared to be normal. The RNA sequencing results of the prefrontal cortex in Fmr1 KO mice indicated that deregulated expression of Foxp2, Tnfsf10, Lepr and other neuronal genes was restored to normal after RA treatment. Gene ontology terms of metabolic processes, extracellular matrix organization and behavioral pathways were enriched. Our findings provided a potential therapeutic intervention for social novelty defects in FXS.
研究领域:
神经科学
·
分子生物学
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遗传学
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产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
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2024
·
IF 9.3
Kai Wang,Shufen Zhang,Yunxia Wang,Xiaomei Wu,Lijuan Wen,Tingting Meng,Xiangyu Jin,Sufen Li,Yiling Hong,Jia Ke,Yichong Xu,Hong Yuan,Fuqiang Hu
Background and purpose Neurodevelopmental disorders (NDDs) are characterized by abnormalities in brain development and neurobehaviors, including autism. The maternal–fetal interface (MFI) is a highly specialized tissue through which maternal factors affect fetal brain development. However, limited research exists on restoring and maintaining MFI homeostasis and its potential impact on NDDs. This study explores the role of placental indoleamine 2,3-dioxygenase (IDO-1) in MFI homeostasis and fetal brain development. Experimental Approach The maternal-fetal barrier was disrupted by sodium valproate (VPA) in pregnant mice, whose offspring show typical autism-like behaviors. Ultrastructural analysis and flow cytometric analysis were conducted to observe the morphological and immune system changes. Behavioral tests and immunofluorescence staining was used to investigate the ability and mechanism of taprenepag to alleviate the abnormal behaviors of VPA-exposed offspring and normalize the development of serotonergic neurons. Key results In VPA-exposed pregnant mice, the downregulation of IDO-1 led to maternal immune overactivation and disruption of maternal-fetal barrier, resulting in excessive 5-HT synthesis in the placenta. This process disrupted the development of the serotonergic neuronal system in the offspring, resulting in impaired development of serotonergic neurons, thalamocortical axons, and NDDs in the progeny. However, a single injection of taprenepag at E13.5 ultimately upregulated placental IDO-1 through amplifying the positive feedback loop COX-2/PGE 2 /PTGER-2/IDO-1 and abolished these alterations. Conclusion Taprenepag improved autism-like behaviors in the offspring of VPA-exposed mice by addressing placental IDO-1 downregulation. This study highlights the potential of targeting IDO-1 to mitigate MFI disruption and NDD development. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-024-03300-7.
研究领域:
神经科学
·
免疫学
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发育生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2025
·
IF 5.2
Honglin Li,Ya Chen,Yue Qiu
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and repetitive, stereotyped behaviors. There is no universally effective pharmacological treatment targeting its core symptoms. Oxytocin, an endogenous polypeptide known as the “social hormone”, has shown potential in improving emotional recognition and social interactions in individuals with ASD. However, its clinical application has been limited due to its short half-life and poor blood–brain barrier penetration. To address these challenges, we utilized peptide lipidation technology to enhance the pharmacokinetic properties and brain bioavailability of oxytocin. A series of lipidated oxytocin analogs was designed and synthesized, exhibiting superior brain distribution and pharmacokinetic profiles in valproic acid-induced autistic rat models compared to unmodified oxytocin. Among these analogs, C16-modified oxytocin (C16-OT), administered intrathecally, achieved the most extensive brain distribution with limited presence in the blood, resulting in long-lasting improvements in autistic behaviors. These improvements, including enhanced social behaviors and reduced stereotypical actions, were sustained for up to 42 days, contrasting with the brief effects typically reported in previous studies. Furthermore, a comparison of administration routes revealed that intrathecal injection achieved higher brain concentrations and more prolonged social behavioral improvements than intranasal delivery. These findings provide robust preclinical evidence that C16-OT, through optimized lipidation and intrathecal delivery, offers sustained central nervous system activity and significant, long-term reversal of social behavioral deficits in rats with autism.
研究领域:
神经科学
·
药理学
·
行为科学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF TOXICOLOGY
·
2025
·
IF 6.9
Hu Liehai,Ren Ke,Li Yichang,Xia Yunhui,Chen Guijuan,Wang Xiaojian,Luo Chunyu,Sun Yun,Li Dongmei
Developmental exposure to environmental pollutants is increasingly recognized as a significant risk factor for autism spectrum disorder (ASD), yet the specific mechanisms by which individual toxicants contribute to this neurodevelopmental disorder remain largely unknown. Methyl ester sulfonate (MES), a widely used anionic surfactant with widespread environmental detection, lacks comprehensive evaluation for developmental neurotoxicity. Here, we exposed pregnant mice to environmentally relevant MES doses (0.06–6 mg/L) from gestational day 8.5 (GD8.5) to postnatal day 21.5 (PND21.5) and assessed their offspring for neurodevelopmental changes. Results showed dose-dependent ASD-like behavioral deficits, including impaired social interactions, heightened anxiety-like behaviors, and increased repetitive/stereotypic patterns. These behavioral anomalies were accompanied by neuropathological alterations, including blood–brain barrier disruption, neuronal loss, and reduced dendritic spine density, indicative of impaired synaptogenesis. Integrative transcriptomic analysis of hippocampal tissue revealed significant dysregulation of key pathways involved in neurodevelopment, prominently featuring the Notch/Hes signaling pathway. Molecular docking simulations suggested that MES could directly interact with Notch receptors, potentially disrupting ligand–receptor interactions. Further in vitro experimental validation demonstrated that MES exposure suppressed neural stem cell differentiation. Collectively, these findings provided evidence that early-life MES exposure acts as a neurodevelopmental toxicant by disrupting Notch/Hes signaling, thereby impairing neuronal differentiation and synaptogenesis, which underlined the observed ASD-like behavioral deficits in mice. This study offers novel mechanistic insights into how environmental factors contribute to ASD pathogenesis and highlights the need for toxicological assessment of widely distributed surfactants.
研究领域:
神经毒理学
·
发育神经科学
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环境毒理学
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分子生物学
·
行为神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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