Down syndrome (DS) is among the most frequent genetic causes of intellectual disability, and ameliorating this deficit is a major goal in support of people with trisomy 21. The Ts65Dn mouse recapitulates some major brain structural and behavioral phenotypes of DS, including reduced size and cellularity of the cerebellum and learning deficits associated with the hippocampus. We show that a single treatment of newborn mice with the sonic hedgehog pathway agonist, SAG1.1 (SAG), results in normal cerebellar morphology in adults. Further, SAG treatment at birth rescued phenotypes associated with hippocampal deficits that occur in untreated adult Ts65Dn mice. This treatment resulted in behavioral improvements and normalized performance in the Morris Water Maze task for learning and memory. SAG treatment also produced physiological effects and partially rescued both NMDA receptor dependent synaptic plasticity and NMDA/AMPA receptor ratio, physiological measures associated with memory. These outcomes confirm an important role for the hedgehog pathway in cerebellar development and raise the possibility for its direct influence in hippocampal function. The positive results from this approach suggest a possible direction for therapeutic intervention to improve cognitive function for this population.
Remarkable advances have been made in recent years towards therapeutics for cognitive impairment in individuals with Down syndrome (DS) by using mouse models. In this review, we briefly describe the phenotypes of mouse models that represent outcome targets for drug testing, the behavioral tests used to assess impairments in cognition and the known mechanisms of action of several drugs that are being used in preclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and in the pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DS research and drug development.
AutDB is a deeply annotated resource for exploring the impact of genetic variations associated with autism spectrum disorders (ASD). First released in 2007, AutDB has evolved into a multi-modular resource of diverse types of genetic and functional evidence related to ASD. Current modules include: Human Gene, which annotates all ASD-linked genes and their variants; Animal Model, which catalogs behavioral, anatomical and physiological data from rodent models of ASD; Protein Interaction (PIN), which builds interactomes from direct relationships of protein products of ASD genes; and Copy Number Variant (CNV), which catalogs deletions and duplications of chromosomal loci identified in ASD. A multilevel data-integration strategy is utilized to connect the ASD genes to the components of the other modules. All information in this resource is manually curated by expert scientists from primary scientific publications and is referenced to source articles. AutDB is actively maintained with a rigorous quarterly data release schedule. As of June 2017, AutDB contains detailed annotations for 910 genes, 2197 CNV loci, 1060 rodent models and 38 296 PINs. With its widespread use by the research community, AutDB serves as a reference resource for analysis of large datasets, accelerating ASD research and potentially leading to targeted drug treatments. AutDB is available at http://autism.mindspec.org/autdb/Welcome.do.
The Ts65Dn mouse is trisomic for orthologs of about half the genes on Hsa21. A number of phenotypes in these trisomic mice parallel those in humans with trisomy 21 (Down syndrome), including cognitive deficits due to hippocampal malfunction that are sufficiently similar to human that “therapies” developed in Ts65Dn mice are making their way to human clinical trials. However, the impact of the model is limited by availability. Ts65Dn cannot be completely inbred and males are generally considered to be sterile. Females have few, small litters and they exhibit poor care of offspring, frequently abandoning entire litters. Here we report identification and selective breeding of rare fertile males from two working colonies of Ts65Dn mice. Trisomic offspring can be propagated by natural matings or by in vitro fertilization (IVF) to produce large cohorts of closely related siblings. The use of a robust euploid strain as recipients of fertilized embryos in IVF or as the female in natural matings greatly improves husbandry. Extra zygotes cultured to the blastocyst stage were used to create trisomic and euploid embryonic stem (ES) cells from littermates. We developed parameters for cryopreserving sperm from Ts65Dn males and used it to produce trisomic offspring by IVF. Use of cryopreserved sperm provides additional flexibility in the choice of oocyte donors from different genetic backgrounds, facilitating rapid production of complex crosses. This approach greatly increases the power of this important trisomic model to interrogate modifying effects of trisomic or disomic genes that contribute to trisomic phenotypes.
Autism (MIM 209850) is a multifactorial disorder with a broad clinical presentation. A number of high-confidence ASD risk genes are known; however, the contribution of non-genetic environmental factors towards ASD remains largely uncertain. Here, we present a bioinformatics resource of genetic and induced models of ASD developed using a shared annotation platform. Using this data, we depict the intricate trends in the research approaches to analyze rodent models of ASD. We identify the top 30 most frequently studied phenotypes extracted from rodent models of ASD based on 787 publications. As expected, many of these include animal model equivalents of the “core” phenotypes associated with ASD, such as impairments in social behavior and repetitive behavior, as well as several comorbid features of ASD including anxiety, seizures, and motor-control deficits. These phenotypes have also been studied in models based on a broad range of environmental inducers present in the database, of which gestational exposure to valproic acid (VPA) and maternal immune activation models comprising lipopolysaccharide (LPS) and poly I:C are the most studied. In our unique dataset of rescue models, we identify 24 pharmaceutical agents tested on established models derived from various ASD genes and CNV loci for their efficacy in mitigating symptoms relevant for ASD. As a case study, we analyze a large collection of Shank3 mouse models providing a high-resolution view of the in vivo role of this high-confidence ASD gene, which is the gateway towards understanding and dissecting the heterogeneous phenotypes seen in single-gene models of ASD. The trends described in this study could be useful for researchers to compare ASD models and to establish a complete profile for all relevant animal models in ASD research.Electronic supplementary materialThe online version of this article (10.1186/s13229-019-0263-7) contains supplementary material, which is available to authorized users.
The APS Journal Legacy Content is the corpus of 100 years of historical scientific research from the American Physiological Society research journals. This package goes back to the first issue of each of the APS journals including the American Journal of Physiology, first published in 1898. The full text scanned images of the printed pages are easily searchable. Downloads quickly in PDF format.
AutDB features a modular framework that aims at collating multifactorial risk factors associated with autism spectrum disorder (ASD). The animal model (AM) module of AutDB was first developed for mouse models of genes and CNVs associated with ASD (Kumar et al., 2011).Subsequently, environmentally induced rodent models were introduced to capture the full spectrum of risk-factors associated with ASD, along with idiopathic models represented by inbred strains. Using the data systematically annotated in AutDB, we depict the intricate trends in the research findings based on rodent models of ASD. We identify the top 30 most frequently studied phenotypes extracted from 911 genetic, 269 induced and 17 inbred rodent models of ASD extracted from 787 publications. As expected, many of these include animal model equivalents of the 'core' phenotypes associated with ASD, as well as several comorbid features of ASD including anxiety, seizures and motor-control deficits. Uniquely, AutDB curates rescue models where various treatment strategies were used in rodent ASD models to alleviate ASDrelevant phenotypes. We further examine ASD models based on 52 genes and 2 CNV loci to identify 24 pharmaceutical agents that were used in 2 or more paradigms for testing their efficacy. As a case study, we analyze various Shank3 mouse models providing a highresolution view of the in vivo role of this high-confidence ASD gene. Together, this resource provides a snapshot of genetic and induced models of ASD within a shared annotation platform to examine the complex meshing of diverse ASD-associated risk-factors.ASD, annotated using a shared and standardized framework. Another distinctive and unique feature of the AutDB resource is the inclusion of rescue models, in which drugs and procedural, genetic or dietary manipulations are used in rodent ASD models in an attempt to rescue ASDrelevant phenotypes. Together, AutDB represents a comprehensive resource including genetic and nongenetic animal models relevant in ASD biology.Using data curated in the AM module over the past 8 years we demonstrate characteristic patterns in analyses undertaken to study genetic and environmentally induced rodent models of ASD. Analysis of trends based on rodent model findings shows that the most frequently assessed phenotypes are related to core features of human ASD such as social interactions, ultrasonic vocalization and repetitive behavior. Additionally, neuroanatomical features like changes in dendritic architecture, observed in post-mortem human studies of ASD brains (Martinez-Cerdeno, 2017), are also frequently examined in rodent models along with electrophysiology conducted on acute brain slices. With a view to facilitating translational research, we highlight pharmaceutical drugs administered to several ASD models. Finally, as a case study, we present a comprehensive analysis of phenotypes studied in rodent models of Shank3, one of the leading genetic risk factors of ASD. Competing interests
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