Early Restoration of<i>Shank3</i>Expression in<i>Shank3</i>Knock-Out Mice Prevents Core ASD-Like Behavioral Phenotypes

Jaramillo, Thomas C.; Xuan, Zhong; Reimers, Jeremy M.; Escamilla, Christine Ochoa; Liu, Shunan; Powell, Craig M.

doi:10.1523/eneuro.0332-19.2020

Cited by 28 publications

(34 citation statements)

References 35 publications

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“…Nonetheless, the knockdown and rescue approaches have been successful in many instances, including in the field of ASD. Re-expression of Shank3 in a Shank3 conditional knock-in mouse model rescued social interaction deficits and attenuated repetitive grooming behavior in adult mice (Mei et al, 2016); early genetic restoration of WT Shank3 in Shank3 E13 mutant mice rescued the same deficits as well as those in locomotion and rearing (Jaramillo et al, 2020). In MeCP2overexpressing mice, reducing MeCP2 level (e.g., by antisense oligonucleotide treatment) reversed behavioral deficits associated with MECP2 duplication syndrome (Sztainberg et al, 2015).…”

Section: Animal Ndd Models Of Asd With Reduced Pv Expression And/or Dmentioning

confidence: 93%

The Parvalbumin Hypothesis of Autism Spectrum Disorder

Filice

Janickova

Henzi

et al. 2020

Front. Cell. Neurosci.

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The prevalence of autism spectrum disorder (ASD)—a type of neurodevelopmental disorder—is increasing and is around 2% in North America, Asia, and Europe. Besides the known genetic link, environmental, epigenetic, and metabolic factors have been implicated in ASD etiology. Although highly heterogeneous at the behavioral level, ASD comprises a set of core symptoms including impaired communication and social interaction skills as well as stereotyped and repetitive behaviors. This has led to the suggestion that a large part of the ASD phenotype is caused by changes in a few and common set of signaling pathways, the identification of which is a fundamental aim of autism research. Using advanced bioinformatics tools and the abundantly available genetic data, it is possible to classify the large number of ASD-associated genes according to cellular function and pathways. Cellular processes known to be impaired in ASD include gene regulation, synaptic transmission affecting the excitation/inhibition balance, neuronal Ca2+ signaling, development of short-/long-range connectivity (circuits and networks), and mitochondrial function. Such alterations often occur during early postnatal neurodevelopment. Among the neurons most affected in ASD as well as in schizophrenia are those expressing the Ca2+-binding protein parvalbumin (PV). These mainly inhibitory interneurons present in many different brain regions in humans and rodents are characterized by rapid, non-adaptive firing and have a high energy requirement. PV expression is often reduced at both messenger RNA (mRNA) and protein levels in human ASD brain samples and mouse ASD (and schizophrenia) models. Although the human PVALB gene is not a high-ranking susceptibility/risk gene for either disorder and is currently only listed in the SFARI Gene Archive, we propose and present supporting evidence for the Parvalbumin Hypothesis, which posits that decreased PV level is causally related to the etiology of ASD (and possibly schizophrenia).

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Section: Animal Ndd Models Of Asd With Reduced Pv Expression And/or Dmentioning

confidence: 93%

The Parvalbumin Hypothesis of Autism Spectrum Disorder

Filice

Janickova

Henzi

et al. 2020

Front. Cell. Neurosci.

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“…reduced to wildtype levels) by restoring Shank3 expression in mice that developed carrying a Shank3 mutation that disrupted most isoforms (Mei et al, 2016). Another recent study showed that an array of behavioral phenotypes could be prevented by rescuing Shank3 expression embryonically (Jaramillo et al, 2020). Taken together with the current study, these results suggest that Shank3 may be required for certain developmental processes, such as synapse formation, that can be triggered later by restoring its expression, but are not lost by disrupting Shank3 expression after development has already occurred.…”

Section: Discussionmentioning

confidence: 99%

Postnatal inactivation of Shank3 expression is insufficient to produce behavioral phenotypes associated with germline deficiency

Hulbert¹,

Yan²,

Wang³

et al. 2020

Preprint

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Background: The developmental origins of Autism Spectrum Disorder (ASD) remain largely unknown. To begin to answer this question, a few studies have implemented conditional gene expression technology to induce or rescue ASD-causing mutations at different times during mouse development. Methods: In the current study, we crossed a ubiquitously-expressed inducible Cre line with mice containing loxP sites surrounding Shank3 exons 4-22 (Shank3 e4-22flox). We then delivered tamoxifen to determine the effects of disrupting Shank3 expression during two different time periods in development. Results: We found that reducing Shank3 expression in fully developed mice had minimal effects on behaviors that are characteristic of the conventional knockout mice. Similarly, disrupting Shank3 expression during an earlier time period (postnatal day 10-21) did not induce behaviors associated with germline deficiency. However, we observed differences in electrophysiological phenotypes for the two groups of conditional knockout mice. Conclusions: Because inducing mutations in adult mice or during early postnatal development is insufficient to cause ASD-like behaviors, Shank3 may play a role even earlier in development, but limited efficiency of the disruption could have contributed to our negative results. We also report considerable mortality when delivering tamoxifen across several different routes of administration, bringing further attention to caution the use of this type of conditional gene expression technology in future studies.

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“…Cre-expression, and thus deletion of Shank3 in neocortical excitatory neurons (ex4-22|ALL-NEX Cre ), Dlx5/6 -positive GABAergic forebrain neurons (ex4-22|ALL-Dlx5/6 Cre ), which include various subclasses of neocortical interneurons but also MSNs as principal striatal projection neurons [ 169 – 174 ], DRD1- (ex4-22|ALL-Drd1 Cre ) and DRD2-positive neurons (ex4-22|ALL-Drd2 Cre ) [ 129 ], did not induce the phenotype previously observed in the constitutive KO model [ 128 ], though it has to be noted that such deficits of constitutive KO mice were also not replicated in this study. Mixed evidence and even conflicting results concerning social interaction deficits were observed in the models ex9|ANK [ 82 , 175 ], ex13|PDZ [ 139 , 176 ], ex21|PRO [ 125 , 177 – 179 ], and the rat model ex6|ANK [ 134 , 180 ]. Intact social motivation and interaction was described in the analysis of the models ex4-7|ANK [ 90 ], ex8|ANK-Q321R [ 132 ], ex21|PRO-InsG3728 [ 126 ], and ex11-21|SH3-PRO in rats [ 135 ].…”

Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

Delling

Boeckers

2021

J Neurodevelop Disord

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Background Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. Main text This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Conclusions Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.

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Early Restoration ofShank3Expression inShank3Knock-Out Mice Prevents Core ASD-Like Behavioral Phenotypes

Abstract: Early restoration of Shank3 expression in Shank3 knockout mice prevents core ASD-like behavioural phenotypes Running Title: Shank3 rescue prevents autism-related phenotypes.

Cited by 28 publications

References 35 publications

The Parvalbumin Hypothesis of Autism Spectrum Disorder

The Parvalbumin Hypothesis of Autism Spectrum Disorder

Postnatal inactivation of Shank3 expression is insufficient to produce behavioral phenotypes associated with germline deficiency

Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

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