Cerebellar and Striatal Pathologies in Mouse Models of Autism Spectrum Disorder

2017 ◽  
pp. 103-119 ◽  
Author(s):  
Saša Peter ◽  
Chris I. De Zeeuw ◽  
Tobias M. Boeckers ◽  
Michael J. Schmeisser
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Models ◽  
Autism Spectrum ◽  
Spectrum Disorder

scholarly journals Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kohei Kitagawa ◽  
Kensuke Matsumura ◽  
Masayuki Baba ◽  
Momoka Kondo ◽  
Tomoya Takemoto ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Model ◽  
Mouse Models ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutation ◽  
Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

scholarly journals Reorganization of Circuits Underlying Cerebellar Modulation of Prefrontal Cortical Dopamine in Mouse Models of Autism Spectrum Disorder

2013 ◽  
Vol 12 (4) ◽  
pp. 547-556 ◽  
Author(s):  
Tiffany D. Rogers ◽  
Price E. Dickson ◽  
Eric McKimm ◽  
Detlef H. Heck ◽  
Dan Goldowitz ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Models ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Prefrontal Cortical

scholarly journals Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder

2017 ◽  
Vol 17 (1) ◽  
pp. 4-22 ◽  
Author(s):  
P.A. Kabitzke ◽  
D. Brunner ◽  
D. He ◽  
P.A. Fazio ◽  
K. Cox ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Models ◽  
Autism Spectrum ◽  
Comprehensive Analysis ◽  
Spectrum Disorder

scholarly journals Comprehensive Analysis of Two Shank3 and the Cacna1c Mouse Models of Autism Spectrum Disorder

2016 ◽  
Author(s):  
Patricia Kabitzke ◽  
Daniela Brunner ◽  
Dansha He ◽  
Pamela A. Fazio ◽  
Kimberly Cox ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Mouse Models ◽  
Gene Mutations ◽  
Behavioral Effect ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Therapeutic Interventions ◽  
General Anxiety ◽  
Background Strain ◽  
Negative Results

AbstractTo expand, analyze and extend published behavioral phenotypes relevant to autism spectrum disorder (ASD), we present a study of three ASD genetic mouse models: Feng’s Shank3tm2Gfng model, hereafter Shank3/F, Jiang’s Shank3tm1Yhj model, hereafter Shank3/J, and the Cacna1c deletion model. The Shank3/F and Shank3/J models mimick gene mutations associated with Phelan-Mcdermid syndrome and the Cacna1c model recapitulates the deletion underlying Timothy syndrome. The current study utilizes both standard and novel, computer-vision based behavioral tests, the same methdology used in our previously published companion report on the Cntnap2 null and 16p11.2 deletion models. Overall, some but not all behaviors replicated published findings. Those that replicated, such as social behavior and overgrooming in Shank3 models, also tended to be milder than previous reports. The Shank3/F model, and to a much lesser extent, the Shank3/J and Cacna1c models, showed hypoactivity and a general anxiety-like behavior triggered by external stimuli which pervaded social interactions. We did not detect deficits in a cognitive procedural learning test nor did we observe perseverative behavior in these models. We did, however, find differences in exploratory patterns of Cacna1c mutant mice suggestive of a behavioral effect in a social setting. In addition, Shank3/F but not Shank3/J KO or Cacna1c HET showed differences in sensory-gating. Discrepancies in our current results from previous reports may be dependent on subtle differences in testing conditions, housing enrichment, or background strain. Both positive and negative results from this study will be useful in identifying the most robust and replicable behavioral signatures within and across mouse models of autism. Understanding these phenotypes may shed light of which features to study when screening compounds for potential therapeutic interventions.

scholarly journals High-throughput screening identifies histone deacetylase inhibitors that modulate GTF2I expression in 7q11.23 microduplication autism spectrum disorder patient-derived cortical neurons

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Francesca Cavallo ◽  
Flavia Troglio ◽  
Giovanni Fagà ◽  
Daniele Fancelli ◽  
Reinald Shyti ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Histone Deacetylase ◽  
Mouse Models ◽  
High Throughput ◽  
High Throughput Screening ◽  
Histone Deacetylase Inhibitors ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Specific Class ◽  
Glutamatergic Neurons

Abstract Background Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition affecting almost 1% of children, and represents a major unmet medical need with no effective drug treatment available. Duplication at 7q11.23 (7Dup), encompassing 26–28 genes, is one of the best characterized ASD-causing copy number variations and offers unique translational opportunities, because the hemideletion of the same interval causes Williams–Beuren syndrome (WBS), a condition defined by hypersociability and language strengths, thereby providing a unique reference to validate treatments for the ASD symptoms. In the above-indicated interval at 7q11.23, defined as WBS critical region, several genes, such as GTF2I, BAZ1B, CLIP2 and EIF4H, emerged as critical for their role in the pathogenesis of WBS and 7Dup both from mouse models and human studies. Methods We performed a high-throughput screening of 1478 compounds, including central nervous system agents, epigenetic modulators and experimental substances, on patient-derived cortical glutamatergic neurons differentiated from our cohort of induced pluripotent stem cell lines (iPSCs), monitoring the transcriptional modulation of WBS interval genes, with a special focus on GTF2I, in light of its overriding pathogenic role. The hits identified were validated by measuring gene expression by qRT-PCR and the results were confirmed by western blotting. Results We identified and selected three histone deacetylase inhibitors (HDACi) that decreased the abnormal expression level of GTF2I in 7Dup cortical glutamatergic neurons differentiated from four genetically different iPSC lines. We confirmed this effect also at the protein level. Limitations In this study, we did not address the molecular mechanisms whereby HDAC inhibitors act on GTF2I. The lead compounds identified will now need to be advanced to further testing in additional models, including patient-derived brain organoids and mouse models recapitulating the gene imbalances of the 7q11.23 microduplication, in order to validate their efficacy in rescuing phenotypes across multiple functional layers within a translational pipeline towards clinical use. Conclusions These results represent a unique opportunity for the development of a specific class of compounds for treating 7Dup and other forms of intellectual disability and autism.

Single administration of resveratrol improves social behavior in adult mouse models of autism spectrum disorder

2020 ◽  
Vol 84 (11) ◽  
pp. 2207-2214 ◽  
Author(s):  
Shizu Hidema ◽  
Shohei Kikuchi ◽  
Ryoji Takata ◽  
Takaaki Yanai ◽  
Kenju Shimomura ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Behavior ◽  
Mouse Models ◽  
Adult Mouse ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Single Administration
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