Modelling Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) Using Mice and Zebrafish

Dougnon, Godfried; Matsui, Hirokazu

doi:10.3390/ijms23147550

Cited by 31 publications

(21 citation statements)

References 325 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another widespread human brain disorder, relatively well modelled in zebrafish, is autism spectrum disorder (ASD) [ 123 ], a complex neurodevelopmental syndrome that manifests as specific deficits in social interactions and as aberrant repetitive behaviors (behavioral perseverations) [ 80 ]. Accordingly, most valid zebrafish models of ASD aim to recapitulate social behavior deficits and/or repetitive behavior.…”

Section: Discussion: Where Next?mentioning

confidence: 99%

“…Accordingly, most valid zebrafish models of ASD aim to recapitulate social behavior deficits and/or repetitive behavior. In contrast to depression and anxiety models, multiple genetic models that disrupts both behavioral axes are available for ASD modelling in zebrafish [ 123 , 124 ]. For example, missense variations of centrosomal protein 41 gene ( cep41 ) that is associated with ASD clinically, disrupt social behavior in zebrafish larvae, also affecting neurodevelopment, axonal growth as well as cranial neural crest cells migration [ 125 ].…”

Section: Discussion: Where Next?mentioning

confidence: 99%

“…A common neurodevelopmental disorder that often overlaps with ASD in terms of symptoms and inherent genetics, attention-deficit/hyperactivity disorder (ADHD), unlike autism, remains poorly studied in zebrafish models [ 123 ]. Clinically, ADHD involves difficulty with paying attention and concentrating, that may also accompany ASD [ 123 ]. Several genes are known to affect zebrafish hyperactivity [ 131 ].…”

Section: Discussion: Where Next?mentioning

confidence: 99%

See 2 more Smart Citations

Current State of Modeling Human Psychiatric Disorders Using Zebrafish

Costa

Колесникова

Galstyan

et al. 2023

IJMS

View full text Add to dashboard Cite

Psychiatric disorders are highly prevalent brain pathologies that represent an urgent, unmet biomedical problem. Since reliable clinical diagnoses are essential for the treatment of psychiatric disorders, their animal models with robust, relevant behavioral and physiological endpoints become necessary. Zebrafish (Danio rerio) display well-defined, complex behaviors in major neurobehavioral domains which are evolutionarily conserved and strikingly parallel to those seen in rodents and humans. Although zebrafish are increasingly often used to model psychiatric disorders, there are also multiple challenges with such models as well. The field may therefore benefit from a balanced, disease-oriented discussion that considers the clinical prevalence, the pathological complexity, and societal importance of the disorders in question, and the extent of its detalization in zebrafish central nervous system (CNS) studies. Here, we critically discuss the use of zebrafish for modeling human psychiatric disorders in general, and highlight the topics for further in-depth consideration, in order to foster and (re)focus translational biological neuroscience research utilizing zebrafish. Recent developments in molecular biology research utilizing this model species have also been summarized here, collectively calling for a wider use of zebrafish in translational CNS disease modeling.

show abstract

Section: Discussion: Where Next?mentioning

confidence: 99%

Section: Discussion: Where Next?mentioning

confidence: 99%

Section: Discussion: Where Next?mentioning

confidence: 99%

See 1 more Smart Citation

Current State of Modeling Human Psychiatric Disorders Using Zebrafish

Costa

Колесникова

Galstyan

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Disruptions of striatal circuits are found in patients with ASD 14,18,19 and ADHD 20 , as well as genetic mouse models for the study of these disorders [54][55][56][57] , and are related to core NDD pathologies, such as dysfunctional reward processing and altered locomotor activity. Of note, a male bias is observed in both human patients with these disorders and some of the respective mouse models.…”

Section: Discussionmentioning

confidence: 99%

Dissecting 16p11.2 hemi-deletion to study sex-specific striatal phenotypes of neurodevelopmental disorders

Abel

Kim

Vanrobaeys

et al. 2023

Preprint

View full text Add to dashboard Cite

Neurodevelopmental disorders (NDDs) are polygenic in nature and copy number variants (CNVs) are ideal candidates to study the nature of this polygenic risk. The disruption of striatal circuits is considered a central mechanism in NDDs. The 16p11.2 hemi-deletion (16p11.2 del) is one of the most common CNVs associated with NDD, and 16p11.2 del/+ mice show sex-specific striatum-related behavioral phenotypes. However, the critical genes among the 27 genes in the 16p11.2 region that underlie these phenotypes remain unknown. Previously, we applied a novel strategy to identify candidate genes associated with the sex-specific phenotypes of 16p11.2 del/+ mice and identified 3 genes of particular importance within the deleted region: thousand and one amino acid protein kinase 2 (Taok2), seizure-related 6 homolog-like 2 (Sez6l2), and major vault protein (Mvp). Using the CRISPR/Cas9 technique, we generated 3 gene hemi-deletion (3g del/+) mice carrying null mutations inTaok2, Sez6l2, and Mvp. We assessed striatum-dependent phenotypes of these 3g del/+ mice in behavioral, molecular, and imaging studies. Hemi-deletion of Taok2, Sez6l2, and Mvp induces sex-specific behavioral alterations in striatum-dependent behavioral tasks, specifically male-specific hyperactivity and impaired motivation for reward seeking, resembling behavioral phenotypes of 16p11.2 del/+ mice. Moreover, RNAseq analysis revealed that 3g del/+ mice exhibit gene expression changes in the striatum similar to 16p11.2 del/+ mice, but only in males. Pathway analysis identified ribosomal dysfunction and translation dysregulation as molecular mechanisms underlying male-specific, striatum-dependent behavioral alterations. Together, the mutation of 3 genes within the 16p11.2 region phenocopies striatal sex-specific phenotypes of 16p11.2 del/+ mice, unlike single gene mutation studies. These results support the importance of a polygenic approach to study NDDs and our novel strategy to identify genes of interest using gene expression patterns in brain regions, such as the striatum, which are impacted in these disorders.

show abstract

“…Similar to that, dopamine transporter (DAT)-knockout mice (ADHD model), show solid face and predictive validity, however, DAT seems to be increased, and not decreased in ADHD patients ( Rahi and Kumar, 2021 ). Finally, ADHD and AD models demonstrate variable positive and negative predictive validity as many drugs that work in animal models ( McKean et al, 2021 ; Dougnon and Matsui, 2022 ; Kantak, 2022 ), unfortunately, show little benefits in humans, while some drugs that are successfully used in patients, fail to improve symptoms in some animal models.…”

Section: Evidence Of the Link Between Attention-deficit Hyperactivity...mentioning

confidence: 99%

From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis

et al. 2023

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common neurodegenerative disorder with the majority of patients classified as sporadic AD (sAD), in which etiopathogenesis remains unresolved. Though sAD is argued to be a polygenic disorder, apolipoprotein E (APOE) ε4, was found three decades ago to pose the strongest genetic risk for sAD. Currently, the only clinically approved disease-modifying drugs for AD are aducanumab (Aduhelm) and lecanemab (Leqembi). All other AD treatment options are purely symptomatic with modest benefits. Similarly, attention-deficit hyperactivity disorder (ADHD), is one of the most common neurodevelopmental mental disorders in children and adolescents, acknowledged to persist in adulthood in over 60% of the patients. Moreover, for ADHD whose etiopathogenesis is not completely understood, a large proportion of patients respond well to treatment (first-line psychostimulants, e.g., methylphenidate/MPH), however, no disease-modifying therapy exists. Interestingly, cognitive impairments, executive, and memory deficits seem to be common in ADHD, but also in early stages of mild cognitive impairment (MCI), and dementia, including sAD. Therefore, one of many hypotheses is that ADHD and sAD might have similar origins or that they intercalate with one another, as shown recently that ADHD may be considered a risk factor for sAD. Intriguingly, several overlaps have been shown between the two disorders, e.g., inflammatory activation, oxidative stress, glucose and insulin pathways, wingless-INT/mammalian target of rapamycin (Wnt/mTOR) signaling, and altered lipid metabolism. Indeed, Wnt/mTOR activities were found to be modified by MPH in several ADHD studies. Wnt/mTOR was also found to play a role in sAD and in animal models of the disorder. Moreover, MPH treatment in the MCI phase was shown to be successful for apathy including some improvement in cognition, according to a recent meta-analysis. In several AD animal models, ADHD-like behavioral phenotypes have been observed indicating a possible interconnection between ADHD and AD. In this concept paper, we will discuss the various evidence in human and animal models supporting the hypothesis in which ADHD might increase the risk for sAD, with common involvement of the Wnt/mTOR-pathway leading to lifespan alteration at the neuronal levels.

show abstract

Modelling Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) Using Mice and Zebrafish

Cited by 31 publications

References 325 publications

Current State of Modeling Human Psychiatric Disorders Using Zebrafish

Current State of Modeling Human Psychiatric Disorders Using Zebrafish

Dissecting 16p11.2 hemi-deletion to study sex-specific striatal phenotypes of neurodevelopmental disorders

From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis

Contact Info

Product

Resources

About