scholarly journals Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models

2020 ◽  
Author(s):  
Sandra Martin Lorenzo ◽  
Valérie Nalesso ◽  
Claire Chevalier ◽  
Marie-Christine Birling ◽  
Yann HERAULT
Keyword(s):  
Locomotor Activity ◽  
Mouse Model ◽  
Learning And Memory ◽  
Mouse Models ◽  
Genetic Background ◽  
Gene Copy Number ◽  
Chronic Administration ◽  
Autism Spectrum ◽  
Gene Copy ◽  
Homologous Region

Abstract Background: Gene copy number variants play an important role in the occurrence of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in 16p11.2 deletion through the regulation of the RHOA pathway. Methods: Here, we generated a new mouse model with a small deletion of two key exons in Kctd13. Then, we targeted the RHOA pathway to rescue the cognitive phenotypes of the Kctd13 and 16p11.2 deletion mouse models in a pure genetic background. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase (ROCK), for six weeks in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 homologous region. Results: We found that the small Kctd13 heterozygous deletion induced a cognitive phenotype similar to the whole deletion of the 16p11.2 homologous region, in the Del/+ mice. We then showed that chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, learning and memory improvement occurred in parallel to change in the RHOA pathway. Limitations: The Kcdt13 mutant line does not recapitulate all the phenotypes found in the 16p11.2 Del/+ model. In particular, the locomotor activity was not altered at 12 and 18 weeks of age and the object location memory was not defective in 18-week old mutants. Similarly, the increase in locomotor activity was not modified by the treatment in the 16p11.2 Del/+ mouse model, suggesting that other loci were involved in such defects. Rescue was observed only after four weeks of treatment but no long-term experiment has been carried out so far. Finally, we did not check the social behaviour, which requires working in another hybrid genetic background.Conclusion: These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the relevance of the RHOA pathway as a therapeutic path for 16p11.2 deletion. In addition, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.

scholarly journals Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sandra Martin Lorenzo ◽  
Valérie Nalesso ◽  
Claire Chevalier ◽  
Marie-Christine Birling ◽  
Yann Herault
Keyword(s):  
Locomotor Activity ◽  
Mouse Model ◽  
Learning And Memory ◽  
Mouse Models ◽  
Genetic Background ◽  
Gene Copy Number ◽  
Chronic Administration ◽  
Autism Spectrum ◽  
Gene Copy ◽  
Homologous Region

Abstract Background Gene copy number variants play an important role in the occurrence of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in 16p11.2 deletion through the regulation of the RHOA pathway. Methods Here, we generated a new mouse model with a small deletion of two key exons in Kctd13. Then, we targeted the RHOA pathway to rescue the cognitive phenotypes of the Kctd13 and 16p11.2 deletion mouse models in a pure genetic background. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase, for six weeks in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 homologous region. Results We found that the small Kctd13 heterozygous deletion induced a cognitive phenotype similar to the whole deletion of the 16p11.2 homologous region, in the Del/+ mice. We then showed that chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, learning and memory improvement occurred in parallel to change in the RHOA pathway. Limitations The Kcdt13 mutant line does not recapitulate all the phenotypes found in the 16p11.2 Del/+ model. In particular, the locomotor activity was not altered at 12 and 18 weeks of age and the object location memory was not defective in 18-week old mutants. Similarly, the increase in locomotor activity was not modified by the treatment in the 16p11.2 Del/+ mouse model, suggesting that other loci were involved in such defects. Rescue was observed only after four weeks of treatment but no long-term experiment has been carried out so far. Finally, we did not check the social behaviour, which requires working in another hybrid genetic background. Conclusion These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the relevance of the RHOA pathway as a therapeutic path for 16p11.2 deletion. In addition, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.

scholarly journals Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models

2020 ◽  
Author(s):  
Sandra Martin Lorenzo ◽  
Valérie Nalesso ◽  
Claire Chevalier ◽  
Marie-Christine Birling ◽  
Yann HERAULT
Keyword(s):  
Locomotor Activity ◽  
Learning And Memory ◽  
Mouse Models ◽  
Genetic Background ◽  
Copy Number Variants ◽  
Gene Copy Number ◽  
Chronic Administration ◽  
Autism Spectrum ◽  
Gene Copy ◽  
Homologous Region

Abstract Background Gene copy number variants have an important role in the appearance of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in the 16p11.2 deletion through the regulation of the RHOA pathway. Methods Here, we generated a new mouse models with a small deletion of two key exons in Kctd13. Then we targeted the RHOA pathway to rescue the cognitive phenotypes of the Kctd13 and 16p11.2 deletion mouse models in a pure genetic background. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase (ROCK), for several days, in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 homologous region. Results We found that the small Kctd13 heterozygous deletion induced similar cognitive phenotype to the whole deletion of the 16p11.2 homologous region, in the Del/+ mice. Then we showed the chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, the learning and memory improvement was parallel to change in the RHOA pathway. Limitations: The Kcdt13 mutant line does not recapitulate all the phenotypes found in the 16p11.2 Del/+ model. In particular the locomotor activity was not altered at 12 and 18 weeks of age and the object location memory was not defective in 18 weeks old mutants. Similarly, the increased in locomotor activity was not modified by the treatment in the 16p11.2 Del/+ mouse model suggesting other loci involved in such defects. Then, the rescue was only observed after four weeks of treatment but no long term experiment has been done so far. Finally we did not check the social behaviour that require to work in another hybrid genetic background. Conclusion These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the relevance of the RHOA pathway as a therapeutic path for the 16p11.2 deletion. Nevertheless, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.

scholarly journals Targeting the RHOA pathway improves learning and memory in Kctd13 and 16p11.2 deletion mouse models

2020 ◽  
Author(s):  
Sandra Martin Lorenzo ◽  
Valérie Nalesso ◽  
Claire Chevalier ◽  
Marie-Christine Birling ◽  
Yann Herault
Keyword(s):  
Object Recognition ◽  
Recognition Memory ◽  
Mouse Models ◽  
Copy Number Variants ◽  
Gene Copy Number ◽  
Chronic Administration ◽  
Autism Spectrum ◽  
Gene Copy ◽  
List Type ◽  
Object Recognition Memory

ABSTRACTGene copy number variants (CNV) have an important role in the appearance of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in the 16p11.2 deletion through the regulation of the RHOA pathway. Here, we target the pathway and rescue the cognitive phenotypes of the 16p11.2 deletion mouse models. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase (ROCK), in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 region. We focused our attention on the most robust cognitive phenotypes seen in the 16p11.2 models and we showed that a chronic fasudil treatment can restore object recognition memory in both mouse models but does not change other behavioural traits. These findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the pertinence of the RHOA pathway as a therapeutic path and reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 CNV models.HIGHLIGHTS- Kctd13 haploinsufficiency recapitulates most of the behaviour phenotypes found in the 16p11.2 Del/+ models- Fasudil treatment restores Kctd13 and 16p11.2 Del/+ mutant phenotypes in novel location and novel object recognition memory tests- Fasudil treatment restores the RhoA pathway in Kctd13+/- and 16p11.2 Del/+ models

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.

Abnormal neurogensis in the hippocampus of a mouse model of fragile X syndromes

2007 ◽  
Vol 30 (4) ◽  
pp. 80
Author(s):  
B Eadie ◽  
B Christie
Keyword(s):  
Mouse Model ◽  
Learning And Memory ◽  
Fragile X Syndrome ◽  
Knockout Mice ◽  
Fragile X ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Fmr1 Gene ◽  
Learning Impairment

Fragile X syndrome is the most common inherited form of mental retardation. It is a neurodevelopmental disorder that is similar in clinical presentation to autism spectrum disorder. However, unlike autism, Fragile X syndrome is caused by the silencing of a single gene, and in recent years, a mouse model of Fragile X syndrome has been generated by deletion of the Fmr1 gene. Surprisingly, a clear neurobiological basis for the learning impairment observed in both these knockout mice and patients has been difficult to elucidate. We hypothesized that neurogenesis, a process that continues into adulthood in the hippocampus, may be abnormal in this syndrome. Support for such a hypothesis comes from the findings that these new neurons may disproportionately contribute to synaptic plasticity in networks engaged during learning and memory. We have shown that the survival of new cells in the hippocampus of young Fmr1 knockout mice is significantly decreased in the ventral hippocampus, a sub-region which may be more involved with emotional, rather than, spatial memory. Further experiments are being conducted to assess the differentiation of these new cells into neurons and glia. We are also characterizing the normal expression of the Fmr1 gene product, FMRP, across the phases of neurogenesis in control mice. In conclusion, we have discovered a clear impairment in a process that may be critical to emotionally-significant learning and memory in a mouse model of Fragile X syndrome.

scholarly journals Computational identification of variables in neonatal vocalizations predictive for postpubertal social behaviors in a mouse model of 16p11.2 deletion

2021 ◽  
Author(s):  
Mitsuteru Nakamura ◽  
Kenny Ye ◽  
Mariel Barbachan e Silva ◽  
Takahira Yamauchi ◽  
Daniel J. Hoeppner ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Hidden Variables ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Individual Variability ◽  
Phenotypic Characterization ◽  
Olfactory Responses ◽  
Hemizygous Deletion ◽  
The Impact

AbstractAutism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD. However, many technical issues have confounded the phenotypic characterization of such mouse models, including systematically biased genetic backgrounds and weak or absent behavioral phenotypes. To address these issues, we developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion and applied computational approaches to identify hidden variables within neonatal vocalizations that have predictive power for postpubertal dimensions relevant to ASD. After variables of neonatal vocalizations were selected by least absolute shrinkage and selection operator (Lasso), random forest, and Markov model, regression models were constructed to predict postpubertal dimensions relevant to ASD. While the average scores of many standard behavioral assays designed to model dimensions did not differentiate a model of 16p11.2 hemizygous deletion and wild-type littermates, specific call types and call sequences of neonatal vocalizations predicted individual variability of postpubertal reciprocal social interaction and olfactory responses to a social cue in a genotype-specific manner. Deep-phenotyping and computational analyses identified hidden variables within neonatal social communication that are predictive of postpubertal behaviors.

Novel hemophilia B mouse models exhibiting a range of mutations in the Factor IX gene

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2767-2774 ◽  
Author(s):  
Denise E. Sabatino ◽  
Elina Armstrong ◽  
Shyrie Edmonson ◽  
Yi-Lin Liu ◽  
Marc Pleimes ◽  
...  
Keyword(s):  
Mouse Models ◽  
Viral Vector ◽  
Translation Termination ◽  
Gene Copy Number ◽  
Large Deletion ◽  
Factor Ix ◽  
Hemophilia B ◽  
Gene Copy ◽  
Missense Mutations ◽  
Gene Deletions

Abstract Animal models have been critical to the development of novel therapeutics in hemophilia. A deficiency of current murine models of hemophilia B is that they are all due to gene deletions, a type of mutation that is relatively rare in the human hemophilia population. We generated mice with a range of mutations in the Factor IX (F.IX) gene; these more faithfully reflect the types of mutations that cause disease in the human population. Transgenic mice expressing either wild-type human F.IX (hF.IX), or F.IX variants with premature translation termination codons, or missense mutations, under the control of the murine transthyretin promoter, were generated and crossed with mice carrying a large deletion of the murine F.IX gene. Gene copy number, F.IX transcript levels in the liver, intrahepatocyte protein expression, and circulating levels of F.IX protein in the mice were determined and compared with data generated by transient transfection assays using the same F.IX variants. Mice were injected with a viral vector expressing hF.IX and displayed a range of immune responses to the transgene product, depending on the underlying mutation. These new mouse models faithfully mimic the mutations causing human disease, and will prove useful for testing novel therapies for hemophilia. (Blood. 2004;104:2767-2774)

scholarly journals Electrobehavioral phenotype and seizure pharmacosensitivity in a novel mouse model of patient-derived SLC6A1 S295L mutation-associated neurodevelopmental epilepsy

2021 ◽  
Author(s):  
Britta E. Lindquist ◽  
Yuliya Voskobiynyk ◽  
Jeanne T. Paz
Keyword(s):  
Mouse Model ◽  
Membrane Trafficking ◽  
Gene Copy Number ◽  
Absence Epilepsy ◽  
Dose Effect ◽  
Inhibitory Neurons ◽  
Gene Copy ◽  
Preclinical Model ◽  
Acute Administration ◽  
Behavioral Performance

Solute carrier family 6 member 1 (SLC6A1) gene encodes GAT-1, a GABA transporter expressed on glia and presynaptic terminals of inhibitory neurons. Mutations in SLC6A1 are associated with myoclonic atonic epilepsy, absence epilepsy, autism, and intellectual disability. However, the mechanisms leading to these defects are unknown. Here, we used a novel mouse model harboring a point mutation (S295L) recently identified in the human SLC6A1 gene that results in impaired membrane trafficking of the GAT-1 protein. We performed chronic wireless telemetry recordings of heterozygous (GAT-1S295L/+) mice, and of mice lacking one or both copies of the Slc6a1 gene (GAT-1+/- and GAT-1-/-). We assessed their behaviors and pharmacosensitivity, and investigated the relationship between seizure burden and behavioral performance. GAT-1S295L/+ mice exhibited frequent spike-wave discharges (SWDs) associated with behavioral arrest, and there was a dose-effect relationship between GAT-1 gene copy number and the severity of electrocorticogram (ECoG) abnormalities. Seizure burden was inversely correlated with behavioral performance. Forelimb grip strength was reduced in female mice. Acute administration of GAT-1 antagonist NO-711 induced SWDs in wild-type mice, exacerbated the phenotype in GAT-1S295L/+ and GAT-1+/- mice, and had no effect on GAT-1-/- mice lacking the drug target. By contrast, ethosuximide normalized the ECoG in GAT-1S295L/+ and GAT-1+/- mice. In conclusion, GAT-1S295L/+ mice show haploinsufficiency with evidence of GAT-1 hypofunction. This mouse model reconstitutes major aspects of human disease and thus provides a useful preclinical model for drug screening and gene therapy.

scholarly journals Behavioral phenotyping of an improved mouse model of Phelan-McDermid Syndrome with a complete deletion of the Shank3 gene

2018 ◽  
Author(s):  
Elodie Drapeau ◽  
Mohammed Riad ◽  
Yuji Kajiwara ◽  
Joseph D. Buxbaum
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Face Validity ◽  
Intermediate Phenotype ◽  
Adult Mice ◽  
Core Symptoms ◽  
Complete Deletion

AbstractPhelan-McDermid Syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability, and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms. Here, we report the production and thorough behavioral characterization of a new mouse model in which all Shank3 isoforms are disrupted. Our mice are more severely affected than previously published models. While the deficits were typically more pronounced in homozygotes, an intermediate phenotype was observed for heterozygotes in many paradigms. As in other Shank3 mouse models, stereotypies, including increased grooming, were observed. Additionally, both sensory and motor deficits were detected in neonatal and adult mice. While social behaviors were not strongly impacted, Shank3-deficient mice displayed a strong escape behavior and avoidance of inanimate objects indicating increased novelty-induced anxiety. Similarly, increased freezing was observed during fear conditioning training and amygdala-dependent cued retrieval. Finally, deficits were observed in both initial training and reversal in the Barnes maze and in contextual fear memory that are memory tasks involving hippocampal-prefrontal circuits. This new mouse model of PMS, engineered to most closely represent human mutations, recapitulates core symptoms of PMS providing improvements for both construct and face validity, compared to previous models.Significant statementPhelan-McDermid syndrome, caused by happloinsufficiency of Shank3, is a severe and complex neurodevelopmental disorder. This study investigates the behavioral consequences of a disruption of all Shank3 isoforms in neonatal and adult mice using a detailed battery of tests tailored to investigate core symptoms and usual comorbidities of PMS. We found that our new model is more severely affected than previously published mouse models with only partial deletions of Shank3 and more closely recapitulates symptoms of PMS thus providing improvements for both construct and face validity. Our results highlight the significance of using a mouse model with a complete deletion of Shank3 for studying mechanisms underlying autism spectrum disorder and PMS, carrying preclinical studies and testing test novel therapeutic approaches.

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