Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function

Jaramillo, Thomas C.; Speed, Haley E.; Xuan, Zhong; Reimers, Jeremy M.; Escamilla, Christine Ochoa; Weaver, Travis; Liu, Shunan; Filonova, Irina; Powell, Craig M.

doi:10.1002/aur.1664

Cited by 94 publications

(142 citation statements)

References 61 publications

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“…These mice harbor the Shank3 mutation in the PDZ domain and were reported to display remarkably high levels of repetitive self-grooming and social deficits [16]. Of note, similar results were reported by Craig Powell and coworkers using a different genetic manipulation of the Shank3 gene [19]. Our larger goal for the present report and for related PACT studies is to identify behavioral phenotypes that replicate consistently in independent cohorts of mice within and between laboratories, in order to strengthen the use of preclinical mouse models of ASD, (a) for understanding the mechanistic underpinnings of ASD-relevant phenotypes, and (b) for preclinical translation in evaluating the therapeutic potential of novel treatments.…”

Section: Discussionmentioning

confidence: 52%

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

et al. 2017

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BackgroundAutism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice.MethodsIn vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant (Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays.ResultsRelative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory.ConclusionsRobust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong...

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Section: Discussionmentioning

confidence: 52%

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

et al. 2017

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“…Disruption of Shank3B expression did not result in gross neurobiological differences in hippocampal or white matter volume, at least as measured here. Previous studies have established a decrease in NMDAR‐mediated hippocampal LTP in Shank3 KOs (Bozdagi et al, 2010; Wang et al, 2011; Yang et al, 2012; Kouser et al, 2013; Jaramillo et al, 2017). Shank3 is also involved in controlling actin dynamics and glutamate receptor‐mediated synaptic transmission and plasticity (Peça et al, 2011; Verpelli et al, 2011; Durand et al, 2012; Duffney et al, 2013; Chana et al, 2015; Sarowar and Grabrucker, 2016).…”

Section: Discussionmentioning

confidence: 99%

Shank3B mutant mice display pitch discrimination enhancements and learning deficits

Rendall

Perrino

Buscarello

et al. 2018

Intl J of Devlp Neuroscience

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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a core set of atypical behaviors in social‐communicative and repetitive‐motor domains. Individual profiles are widely heterogeneous and include language skills ranging from nonverbal to hyperlexic. The causal mechanisms underlying ASD remain poorly understood but appear to include a complex combination of polygenic and environmental risk factors. SHANK3 (SH3 and multiple ankyrin repeat domains 3) is one of a subset of well‐replicated ASD‐risk genes (i.e., genes demonstrating ASD associations in multiple studies), with haploinsufficiency of SHANK3 following deletion or de novo mutation seen in about 1% of non‐syndromic ASD. SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. In order to more closely evaluate the contribution of SHANK3 to neurodevelopmental expression of ASD, a knockout mouse model with a mutation in the PDZ domain was developed. Initial research showed compulsive/repetitive behaviors and impaired social interactions in these mice, replicating two core ASD features. The current study was designed to further examine Shank3B heterozygous and homozygous knockout mice for behaviors that might map onto atypical language in ASD (e.g., auditory processing, and learning/memory). We report findings of repetitive and atypical aggressive social behaviors (replicating prior reports), novel evidence that Shank3B KO mice have atypical auditory processing (low‐level enhancements that might have a direct relationship with heightened pitch discrimination seen in ASD), as well as robust learning impairments.

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“…Shank3 deletions in mice produce social deficits, stereotypic behavior and aberrant cortical and striatal synaptic neurotransmission [68–70]. There is evidence that in these models the PV+ circuitry has a reduction in its perineuronal net over PC cells, resulting in a dysregulation in cortical networks due to an E/I imbalance [71].…”

Section: Pre-clinical Models Of Asd and Ts With Interneuronal Alteratmentioning

confidence: 99%

The Role of Interneurons in Autism and Tourette Syndrome

Rapanelli

Frick

Pittenger

2017

Trends in Neurosciences

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The brain includes multiple types of interconnected excitatory and inhibitory neurons that together allow us to move, think, feel and interact with the environment. Inhibitory interneurons comprise a small, heterogeneous fraction, but they exert a powerful and tight control over neuronal activity and consequently modulate the magnitude of neuronal output and, ultimately, information processing. Interneuronal abnormalities are linked to two pediatric psychiatric disorders with high comorbidity: autism and Tourette syndrome. Studies probing the basis of this link have been contradictory regarding whether the causative mechanism is a reduction in number, dysfunction or gene aberrant expression (or a combination thereof). Here, we integrate different theories into a more comprehensive view of interneurons as responsible for the symptomatology observed in these disorders.

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Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function

Cited by 94 publications

References 61 publications

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

Shank3B mutant mice display pitch discrimination enhancements and learning deficits

The Role of Interneurons in Autism and Tourette Syndrome

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