Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice

Tsai, Peter T.; Hull, Court; Chu, YunXiang; Greene‐Colozzi, Emily; Sadowski, Abbey R.; Leech, Jarrett M.; Steinberg, Jason; Crawley, Jacqueline N.; Regehr, Wade G.; Şahin, Mustafa

doi:10.1038/nature11310

Cited by 799 publications

(951 citation statements)

References 39 publications

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“…Indeed, many cell-signalling pathways are under investigation in relation to ASDs, especially the ones that have already been much studied for their synaptic functions [13 -16]. Suspected brain regions also are widely diverse and range from the prefrontal cortex to cerebellum [17,18].…”

Section: Introductionmentioning

confidence: 99%

Shank mutant mice as an animal model of autism

Yoo

Bakes

Bradley

et al. 2014

Phil. Trans. R. Soc. B

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In this review, we focus on the role of the Shank family of proteins in autism. In recent years, autism research has been flourishing. With genetic, molecular, imaging and electrophysiological studies being supported by behavioural studies using animal models, there is real hope that we may soon understand the fundamental pathology of autism. There is also genuine potential to develop a molecular-level pharmacological treatment that may be able to deal with the most severe symptoms of autism, and clinical trials are already underway. The Shank family of proteins has been strongly implicated as a contributing factor in autism in certain individuals and sits at the core of the alleged autistic pathway. Here, we analyse studies that relate Shank to autism and discuss what light this sheds on the possible causes of autism.

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Section: Introductionmentioning

confidence: 99%

Shank mutant mice as an animal model of autism

Yoo

Bakes

Bradley

et al. 2014

Phil. Trans. R. Soc. B

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“…Similarly deviant vocalizations have also been observed in Fmr1‐ and Tsc1‐ deficient pups, therefore our results contribute to a consistency of communication deficits found across several mTOR models (Reynolds et al., 2016; Tsai et al., 2012; Young, Schenk, Yang, Jan, & Jan, 2010). Specifically, Fmr1 KO pups were shown to emit significantly fewer vocalizations than their WT counterparts when separated from their mother (Reynolds et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, Fmr1 KO pups were shown to emit significantly fewer vocalizations than their WT counterparts when separated from their mother (Reynolds et al., 2016). In contrast, Tsc1 HT pups emitted significantly more vocalizations than their controls (Tsai et al., 2012). Thus, while the particular quantity of vocalizations emitted is not always constant across different mTOR models, the underlying aberrant vocalizing patterns are still observed, demonstrating a consistency between our findings and those in related studies.…”

Section: Discussionmentioning

confidence: 99%

“…Next, they were removed from their dam in the room temperature home cage and the pups were put into a clean, preheated cage. We then individually tested each mouse by removing the mouse from the warmed cage and placing it in another 22°C cage, as detailed in numerous other studies (Scattoni et al., 2008; Shair, 2007; Tsai et al., 2012). The mouse was then placed within a 40 cm × 40 cm × 30 cm sound‐attenuated chamber.…”

Section: Methodsmentioning

confidence: 99%

“…They can be emitted when a pup is separated from its parents, during social play, and are used during courtship and mating rituals, in addition to social investigation in adult mice (D'Amato, Scalera, Sarli, & Moles, 2005; Nyby, 1983; Panksepp et al., 2007). Research also suggests that altered USVs are an important component of the phenotype for various neurodevelopmental conditions, including ASD, Fragile X, and tuberous sclerosis complex (Reynolds, Nolan, Jefferson, & Lugo, 2016; Scattoni, Gandhy, Ricceri, & Crawley, 2008; Tsai et al., 2012). …”

Section: Introductionmentioning

confidence: 99%

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NS‐Pten knockout mice show sex‐ and age‐specific differences in ultrasonic vocalizations

Binder

Lugo

2017

Brain and Behavior

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ObjectiveThe goal of this study was to identify changes in quantitative and qualitative aspects of neonatal ultrasonic vocalizations USVs in neuron‐subset specific (NS‐Pten) knockout males and females when compared with wild‐type male and female mice.BackgroundOne signaling cascade that plays a crucial role in the development of an autistic‐like phenotype is the PI3K/Akt/mTOR pathway. Mouse models that illustrate this connection include Fmr1, Tsc1, and NS‐Pten‐deficient mice. While numerous studies have investigated ultrasonic vocalizations in Fmr1 knockout and Tsc1 heterogenous mice, none have investigated USVs in NS‐Pten knockout mice using a full spectrum recording system.MethodsWe recorded ultrasonic vocalizations from NS‐Pten wild‐type and knockout male and female mice on postnatal days 8 and 11. On these days, we measured the number and quality of calls emitted from pups when they were removed from their mothers.ResultsWe found that knockout pups emitted fewer vocalizations for both sexes (p < .05). Knockout males had calls of a shorter duration and lower peak amplitude on day 8, while showing a shorter duration, lower peak amplitude, and higher peak and fundamental frequency on day 11 (p < .001). Knockout females vocalized at a lower peak amplitude and fundamental frequency, and a higher peak frequency on day 8, while showing a shorter duration and a higher peak and fundamental frequency on day 11 (p < .001). Spectrographic analyses also revealed significant differences in call type for both genotypes and sexes (p < .05).ConclusionsThese findings demonstrate that deletion of NS‐Pten results in significant decreases in vocalizations across both sexes. Additionally, our findings indicate that the aberrant vocalizations and increased call duration seen in other mTOR models are also present in NS‐Pten knockout mice. Our study provides evidence of a connection between hyperactive mTOR signaling and neonatal ultrasonic vocalizations.

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Overview of Mouse Models of Autism Spectrum Disorders

Bey

Jiang

2014

CP Pharmacology

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This overview covers many well-characterized mouse models of autism spectrum disorders (ASDs). As there are numerous mouse models of varying design and description in the literature, the models presented here represent examples of genetically engineered models where human genetic evidence supports a causative relationship between the targeted mutation and the behavioral phenotype of the mouse models. As the diagnosis of ASDs is primarily based on behavioral evaluations in humans, we highlight the murine behavioral analogs to human autistic behaviors in different models. However, because the characteristic behaviors of ASDs in humans are in the domains of social interaction, communication, and restricted interests, the translational value of various behavioral assays used in rodents remains a subject of debate. Using genetically engineered mouse models with good construct and face validity will provide a platform for investigating underlying pathophysiological mechanisms and discovering potential therapeutic interventions which will hopefully translate into effective treatments for ASDs. We also illustrate several significant challenges in the field of modeling ASDs in rodents due to the considerable clinical and molecular heterogeneity associated with ASDs in humans.

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Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice

Cited by 799 publications

References 39 publications

Shank mutant mice as an animal model of autism

Shank mutant mice as an animal model of autism

NS‐Pten knockout mice show sex‐ and age‐specific differences in ultrasonic vocalizations

Overview of Mouse Models of Autism Spectrum Disorders

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