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

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

doi:10.3390/cimb46030121

Cited by 3 publications

(1 citation statement)

References 50 publications

(85 reference statements)

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“…Several rodent models of ASD-like behavior have been developed, to recapitulate human disease phenotype, by eliciting infectious processes prenatally or early postnatally using varieties of biological maneuvers [15,16]. Most frequently, polyinosinic-polycytidylic acid (PolyIC), a double-stranded RNA molecule that stimulates an immune response through the activation of toll-like receptor 3 is widely employed to model autism in rodents [17][18][19]. Lipopolysaccharide (LPS) and propionic acid are also well-documented immunogens used pre-and postnatally to induce autism in rodent models [20][21][22][23].…”

Section: Biological Models Of Autistic-like Behavior: Maternal Immune...mentioning

confidence: 99%

Animal Models of Autistic-Like Behavior: Is the Time for a Scoring System with More Accurate Definitions?

Ornoy,

Echefu,

Becker

2024

Preprint

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Appropriate animal models of human diseases are a cornerstone in the advancement of science and medicine. To create animal models of neuropsychiatric and neurobehavioral diseases such as ASD necessitates the development of sufficient neurobehavioral measuring tools to translate human behavior to expected measurable behavioral features in animals. Indeed, at least in rodents, adequate neurobehavioral and neurological tests have been developed. Since ASD is characterized by a number of specific behavioral trends with significant severity, animal models of autistic-like behavior have to demonstrate the specific characteristic features, namely impaired social interactions, and communication, restricted, repetitive behavioral patterns with association to several additional impairments such as somatosensory, motor and memory impairments. Thus, an appropriate model must show behavioral impairment of a minimal number of neurobehavioral characteristics using an adequate number of behavioral tests. The proper animal models enable the study of ASD like-behavior from the etiologic, pathogenetic and therapeutic aspects. From the etiologic aspects, models have been developed by the use of immunogenic substances like polyinosinic-polycytidylic acid (PolyIC), Lipopolysaccharide (LPS) and propionic acid or other well-documented immunogens or pathogens, like mycobacterium tuberculosis. Another approach is the use of chemicals like valproic acid, Polychlorinated biphenyls (PCBs), organophosphate pesticides - chlorpyrifos (CPF) and others. These substances were administered either prenatally, generally after the period of major organogenesis, or, especially in rodents, during the early postnatal life. In addition, using modern genetic manipulation methods, genetic models have been created of almost all human genetic diseases that are manifested by autistic like behavior (i.e. fragile X, Rett syndrome, SHANK gene mutation Neuroligin genes and others). Ideally, we should not only evaluate the different behavioral modes affected by the ASD-like behavior but also assess the severity of the behavioral deviations by an appropriate scoring system, as applied to humans.

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Section: Biological Models Of Autistic-like Behavior: Maternal Immune...mentioning

confidence: 99%

Animal Models of Autistic-Like Behavior: Is the Time for a Scoring System with More Accurate Definitions?

Ornoy,

Echefu,

Becker

2024

Preprint

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Dysregulation of the mTOR-FMRP pathway and synaptic plasticity in an environmental model of ASD

Hilal,

Rosina,

Pedini

et al. 2024

Mol Psychiatry

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Autism Spectrum Disorder (ASD) is caused by genetic, epigenetic, and environmental factors. Mutations in the human FMR1 gene, encoding the Fragile X Messenger Ribonucleoprotein 1 (FMRP), cause the most common monogenic form of ASD, the Fragile X Syndrome (FXS). This study explored the interaction between the FMR1 gene and a viral-like infection as an environmental insult, focusing on the impact on core autistic-like behaviors and the mGluR1/5-mTOR pathway. Pregnant heterozygous Fmr1 mouse females were exposed to maternal immune activation (MIA), by injecting the immunostimulant Poly (I:C) at the embryonic stage 12.5, simulating viral infections. Subsequently, ASD-like behaviors were analyzed in the adult offspring, at 8–10 weeks of age. MIA exposure in wild-type mice led to ASD-like behaviors in the adult offspring. These effects were specifically confined to the intrauterine infection, as immune activation at later stages, namely puberty (Pubertal Immune Activation, PIA) at post-natal day 35 or adulthood (Adult Immune Activation, AIA) at post-natal day 56, did not alter adult behavior. Importantly, combining the Fmr1 mutation with MIA exposure did not intensify core autistic-like behaviors, suggesting an occlusion effect. Mechanistically, MIA provided a strong activation of the mGluR1/5-mTOR pathway, leading to increased LTP and downregulation of FMRP specifically in the hippocampus. Finally, FMRP modulates mTOR activity via TSC2. These findings further strengthen the key role of the mGluR1/5-mTOR pathway in causing ASD-like core symptoms.

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Animal Models of Autistic-like Behavior in Rodents: A Scoping Review and Call for a Comprehensive Scoring System

Ornoy,

Echefu,

Becker

2024

IJMS

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Appropriate animal models of human diseases are a cornerstone in the advancement of science and medicine. To create animal models of neuropsychiatric and neurobehavioral diseases such as autism spectrum disorder (ASD) necessitates the development of sufficient neurobehavioral measuring tools to translate human behavior to expected measurable behavioral features in animals. If possible, the severity of the symptoms should also be assessed. Indeed, at least in rodents, adequate neurobehavioral and neurological tests have been developed. Since ASD is characterized by a number of specific behavioral trends with significant severity, animal models of autistic-like behavior have to demonstrate the specific characteristic features, namely impaired social interactions, communication deficits, and restricted, repetitive behavioral patterns, with association to several additional impairments such as somatosensory, motor, and memory impairments. Thus, an appropriate model must show behavioral impairment of a minimal number of neurobehavioral characteristics using an adequate number of behavioral tests. The proper animal models enable the study of ASD-like-behavior from the etiologic, pathogenetic, and therapeutic aspects. From the etiologic aspects, models have been developed by the use of immunogenic substances like polyinosinic-polycytidylic acid (PolyIC), lipopolysaccharide (LPS), and propionic acid, or other well-documented immunogens or pathogens, like Mycobacterium tuberculosis. Another approach is the use of chemicals like valproic acid, polychlorinated biphenyls (PCBs), organophosphate pesticides like chlorpyrifos (CPF), and others. These substances were administered either prenatally, generally after the period of major organogenesis, or, especially in rodents, during early postnatal life. In addition, using modern genetic manipulation methods, genetic models have been created of almost all human genetic diseases that are manifested by autistic-like behavior (i.e., fragile X, Rett syndrome, SHANK gene mutation, neuroligin genes, and others). Ideally, we should not only evaluate the different behavioral modes affected by the ASD-like behavior, but also assess the severity of the behavioral deviations by an appropriate scoring system, as applied to humans. We therefore propose a scoring system for improved assessment of ASD-like behavior in animal models.

show abstract

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

Cited by 3 publications

References 50 publications

Animal Models of Autistic-Like Behavior: Is the Time for a Scoring System with More Accurate Definitions?

Animal Models of Autistic-Like Behavior: Is the Time for a Scoring System with More Accurate Definitions?

Dysregulation of the mTOR-FMRP pathway and synaptic plasticity in an environmental model of ASD

Animal Models of Autistic-like Behavior in Rodents: A Scoping Review and Call for a Comprehensive Scoring System

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