The Notch signaling pathway inhibitor Dapt alleviates autism-like behavior, autophagy and dendritic spine density abnormalities in a valproic acid-induced animal model of autism

Zhang, Yinghua; Xiang, Zhe; Jia, Yunjie; Xue-ling, HE; Wang, Lijun; Cui, Weigang

doi:10.1016/j.pnpbp.2019.109644

Cited by 51 publications

(38 citation statements)

References 53 publications

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“…Similarly, in rodents, VPA induces a robust range of ASD-like behavioral and morphological alterations (reviewed in Chomiak et al, 2013;Roullet et al, 2013;Nicolini and Fahnestock, 2018). Adult rodents exposed to VPA display a reduction of brain autophagy in associations with the behavioral and morphological alterations (Qin et al, 2016;Zhang et al, 2016Zhang et al, , 2019Wu et al, 2018). In line with these results, we found altered autophagic markers, such as decreased LC3Bii and increased p62, in the striatum of P28 mice prenatally exposed to VPA.…”

Section: Discussionsupporting

confidence: 81%

“…Moreover, we discover that at P10 the VPA does not significantly change autophagy. Thus, it seems that prenatal exposure to VPA determines a detectable reduction of striatal autophagy only during the late postnatal development (P28) that it is maintained in the adulthood (Qin et al, 2016;Zhang et al, 2016Zhang et al, , 2019Wu et al, 2018). The lack of detectable change in autophagy at P10 may be the result of the high autophagic flux that masks the impairment in autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, autophagic dysfunction is found in both genetic and environmental animal models of ASD, suggesting its impairment may be a general feature of ASD pathophysiology (Tang et al, 2014;Qin et al, 2016;Zhang et al, 2016Zhang et al, , 2019Wu et al, 2018;Yan et al, 2018). Notably, rodents prenatally exposed to valproic acid (VPA) show a reduction in brain autophagy accompanied by a series of morphological alterations and behavioral impairments consistent with the ASD symptomatology described in patients (Qin et al, 2016;Zhang et al, 2016;Wu et al, 2018;Zhang et al, 2019). Yet, little is known about the developmental regulation of neuronal autophagy and the possible implications for ASD.…”

Section: Introductionmentioning

confidence: 85%

“…Autophagic dysfunction is observed in humans with neurodevelopmental disorders (Lee et al, 2013;Poultney et al, 2013;Byrne et al, 2016;Hor and Tang, 2018), and mouse models with reduced autophagy display phenotypes implicated in autism spectrum disorders (ASD) (Tang et al, 2014;Kim et al, 2017;Yan et al, 2018). Importantly, autophagic dysfunction is found in both genetic and environmental animal models of ASD, suggesting its impairment may be a general feature of ASD pathophysiology (Tang et al, 2014;Qin et al, 2016;Zhang et al, 2016Zhang et al, , 2019Wu et al, 2018;Yan et al, 2018). Notably, rodents prenatally exposed to valproic acid (VPA) show a reduction in brain autophagy accompanied by a series of morphological alterations and behavioral impairments consistent with the ASD symptomatology described in patients (Qin et al, 2016;Zhang et al, 2016;Wu et al, 2018;Zhang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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mTOR Suppresses Macroautophagy During Striatal Postnatal Development and Is Hyperactive in Mouse Models of Autism Spectrum Disorders

Lieberman

Cartocci

Pigulevskiy

et al. 2020

Front. Cell. Neurosci.

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Macroautophagy (hereafter referred to as autophagy) plays a critical role in neuronal function related to development and degeneration. Here, we investigated whether autophagy is developmentally regulated in the striatum, a brain region implicated in neurodevelopmental disease. We demonstrate that autophagic flux is suppressed during striatal postnatal development, reaching adult levels around postnatal day 28 (P28). We also find that mTOR signaling, a key regulator of autophagy, increases during the same developmental period. We further show that mTOR signaling is responsible for suppressing autophagy, via regulation of Beclin-1 and VPS34 activity. Finally, we discover that autophagy is downregulated during late striatal postnatal development (P28) in mice with in utero exposure to valproic acid (VPA), an established mouse model of autism spectrum disorder (ASD). VPA-exposed mice also display deficits in striatal neurotransmission and social behavior. Correction of hyperactive mTOR signaling in VPA-exposed mice restores social behavior. These results demonstrate that neurons coopt metabolic signaling cascades to developmentally regulate autophagy and provide additional evidence that mTOR-dependent signaling pathways represent pathogenic signaling cascades in ASD mouse models that are active during specific postnatal windows.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

mTOR Suppresses Macroautophagy During Striatal Postnatal Development and Is Hyperactive in Mouse Models of Autism Spectrum Disorders

Lieberman

Cartocci

Pigulevskiy

et al. 2020

Front. Cell. Neurosci.

View full text Add to dashboard Cite

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“…The CC2D1A (coiled-coil and C2 domain-containing 1A) gene is one of the new candidate genes associated with autism [4] . In humans, the CC2D1A gene mutation was first associated with autosomal recessive nonsyndromic intellectual disability [97] . This means that the CC2D1A gene has a function in the central nervous system.…”

Section: Cc2d1a Models For Autismmentioning

confidence: 99%

Animal models of autism: a perspective from autophagy mechanisms

Dana¹,

Tahtasakal²,

Şener³

2020

jtgg

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Autism spectrum disorder (ASD) is characterized by impairments in social interaction and the presence of stereotypy and restrictive behavior. The clinical heterogeneity of ASD makes it difficult to explain the mechanisms underlying the disease. In recent years, the association between autophagy and neuropsychiatric diseases has been investigated. In this review, we aimed elucidate the relationship between autism and autophagy mechanism in well-known autism relevant animal models. Autophagy is a cell-protective mechanism that allows cell survival in low nutrient conditions, often through the degradation of aging and damaged proteins and organelles. The target of rapamycin (TOR) complex is activated for the activation of autophagy. Apart from mTOR animal models, the valproic acid model is frequently used in autism studies. The coiled-coil and C2 domain containing 1A (CC2D1A) gene is one of the new candidate genes associated with ASD. In a recent study that used Cc2d1a knockout mice, microtubule-associated protein 1A/1B-light chain 3 (LC3) and Beclin 1 expression levels were dysregulated in the hippocampus. It is thought that the impaired autophagy mechanism contributes to the etiology of ASD. These results showed that CC2D1A acts as a new biological pathway in autophagy. Choosing the right model is crucial for ASD studies, and further progress will be made as these results become available in the clinic. In particular, it is expected that further studies on CC2D1A will provide new information in this field.

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Lenvatinib induces cardiac developmental toxicity in zebrafish embryos through regulation of Notch mediated‐oxidative stress generation

Liu

Huang

Wan

et al. 2022

Environmental Toxicology

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Due to an increasing number of abused drugs dumped into the wastewater, more and more drugs are detected in the water environment, which may affect the survival of aquatic organisms. Lenvatinib is a multi-targeted tyrosine kinase inhibitor, and is clinically used to treat differentiated thyroid cancer, renal epithelial cell carcinoma and liver cancer. However, there are few reports on the effects of lenvatinib in embryos development. In this study, zebrafish embryos were used to evaluate the effect of lenvatinib on cardiovascular development. Well-developed zebrafish embryos were selected at 6 h post fertilization (hpf) and exposed to 0.05 mg/L, 0.1 mg/L and 0.2 mg/L lenvatinib up to 72 hpf. The processed embryos demonstrated cardiac edema, decreased heart rate, prolonged SV-BA distance, inhibited angiogenesis, and blocked blood circulation. Lenvatinib caused cardiac defects in the whole stage of cardiac development and increased the apoptosis of cardiomyocyte.Oxidative stress in the processed embryos was accumulated and inhibiting oxidative stress could rescue cardiac defects induced by lenvatinib. Additionally, we found that lenvatinib downregulated Notch signaling, and the activation of Notch signaling could rescue cardiac developmental defects and downregulate oxidative stress level induced by lenvatinib. Our results suggested that lenvatinib might induce cardiac developmental toxicity through inducing Notch mediated-oxidative stress generation, raising concerns about the harm of exposure to lenvatinib in aquatic organisms.

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The Notch signaling pathway inhibitor Dapt alleviates autism-like behavior, autophagy and dendritic spine density abnormalities in a valproic acid-induced animal model of autism

Cited by 51 publications

References 53 publications

mTOR Suppresses Macroautophagy During Striatal Postnatal Development and Is Hyperactive in Mouse Models of Autism Spectrum Disorders

mTOR Suppresses Macroautophagy During Striatal Postnatal Development and Is Hyperactive in Mouse Models of Autism Spectrum Disorders

Animal models of autism: a perspective from autophagy mechanisms

Lenvatinib induces cardiac developmental toxicity in zebrafish embryos through regulation of Notch mediated‐oxidative stress generation

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