Environmental enrichment has minimal effects on behavior in the Shank3 complete knockout model of autism spectrum disorder

Hulbert, Samuel W; Bey, Alexandra L.; Jiang, Yong‐Hui

doi:10.1002/brb3.1107

Cited by 18 publications

(15 citation statements)

References 47 publications

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“…Shank3 ∆e4-22 -/mice were previously reported to self-groom at signi cantly higher rates compared to wildtype and heterozygous mice (Wang et al, 2016;Bey et al, 2018;Drapeau et al, 2018;Hulbert et al, 2018). Our current study con rms this phenotype in the germline knockout mice, but there were no differences between / AKO mice and their controls or /-AKO mice and their controls (Figure 2A).…”

Section: Adult Knockout Mice Do Not Recapitulate Behavioral Phenotypesupporting

confidence: 75%

“…Delivering tamoxifen to CAGGS-CreER; Shank3 e4-22 ox/ ox mice allows for recombination of the oxed DNA sequences. After putting the CAGGS-CreER; Shank3 e4-22 ox/ ox ( / AKO) mice on a tamoxifencontaining diet for eight weeks, only a modest reduction of Shank3 protein was observed in the postsynaptic density (PSD) fractions of the striatum, in which the highest expression of Shank3 is observed (Wang et al, 2014), compared to controls ( Figure 1A).. We therefore took advantage of the fact that the heterozygous Shank3 ∆e4-22 +/mice show little to no phenotype (Hulbert et al 2018, Wang et al 2016 to induce a deletion of the remaining allele in Shank3 e4-22 ox/mice. After eight weeks on a tamoxifen-containing diet, CAGS-CreER; Shank3 e4-22 ox/-( /-AKO) mice showed a reduction in Shank3 protein approaching germline knockout levels, but this disruption was still not complete and variable ( Figure 1B)..…”

Section: Resultsmentioning

confidence: 99%

“…This raises questions concerning what level of Shank3 suppression is su cient to produce these phenotypes. In human patients, missing one copy of the SHANK3 gene is typically su cient to produce a severe diagnosis of ASD (Durand et al, 2007;Moessner et al, 2007;Boccuto et al, 2013;Soorya et al, 2013), but across multiple studies in our laboratory and others, the majority of mice heterozygous for Shank3 have a mild or no phenotype with few exceptions (Bozdagi et al, 2010;Peça et al, 2011;Wang et al, 2011;Schmeisser et al, 2012;Kouser et al, 2013;Duffney et al, 2015;Lee et al, 2015;Speed et al, 2015;Jaramillo et al, 2016;Wang et al, 2016;Zhou et al, 2016;Jaramillo et al, 2017;Drapeau et al, 2018;Hulbert et al, 2018). This problem is common among genetic mutant ASD mouse models (Hulbert and Jiang, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…However, much remains to be discovered regarding the developmental pathogenesis of the disorder. The Shank3 mouse model of ASD is well-suited to determine whether disruptions to synaptic development contribute to ASD pathogenesis because in vitro studies have directly linked Shank3 to the formation of synapses (Roussignol et al, 2005) and in vivo studies utilizing conventional knockouts have presented synaptic de cits along with multiple ASD-like and comorbid behavioral phenotypes (Bozdagi et al, 2010;Peça et al, 2011;Wang et al, 2011;Duffney et al, 2013;Kouser et al, 2013;Drapeau et al, 2014;Duffney et al, 2015;Lee et al, 2015;Speed et al, 2015;Jaramillo et al, 2016;Wang et al, 2016;Zhou et al, 2016;Jaramillo et al, 2017;Drapeau et al, 2018;Hulbert et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Adult Knockout Mice Do Not Recapitulate Behavioral Phenotypesupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Hulbert¹,

Yan²,

Wang³

et al. 2020

Preprint

Self Cite

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“…For example, a mouse model lacking exon 4–9 of Shank3 exhibited object recognition deficits [ 104 ]. Another study with full Shank3 deletion showed increased anxiety-like behavior of knock-out and heterozygous animals compared to wild-type animals [ 105 ]. Another group reported impaired contextual fear learning in the Shank3 knock-out mouse model [ 106 ].…”

Section: The Critical Role Of Rich2 In Fear Modulationmentioning

confidence: 99%

Rho GTPases in the Amygdala—A Switch for Fears?

Sarowar

Grabrucker

2020

Cells

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Fear is a fundamental evolutionary process for survival. However, excess or irrational fear hampers normal activity and leads to phobia. The amygdala is the primary brain region associated with fear learning and conditioning. There, Rho GTPases are molecular switches that act as signaling molecules for further downstream processes that modulate, among others, dendritic spine morphogenesis and thereby play a role in fear conditioning. The three main Rho GTPases—RhoA, Rac1, and Cdc42, together with their modulators, are known to be involved in many psychiatric disorders that affect the amygdala′s fear conditioning mechanism. Rich2, a RhoGAP mainly for Rac1 and Cdc42, has been studied extensively in such regard. Here, we will discuss these effectors, along with Rich2, as a molecular switch for fears, especially in the amygdala. Understanding the role of Rho GTPases in fear controlling could be beneficial for the development of therapeutic strategies targeting conditions with abnormal fear/anxiety-like behaviors.

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Sex‐dependent influence of postweaning environmental enrichment in Angelman syndrome model mice

et al. 2022

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Introduction: Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by mutation or loss of UBE3A and marked by intellectual disability, ataxia, autism-like symptoms, and other atypical behaviors. One route to treatment may lie in the role that environment plays early in postnatal life. Environmental enrichment (EE) is one manipulation that has shown therapeutic potential in preclinical models of many brain disorders, including neurodevelopmental disorders. Here, we examined whether postweaning EE can rescue behavioral phenotypes in Ube3a maternal deletion mice (AS mice), and whether any improvements are sex-dependent.Methods: Male and female mice (C57BL/6J Ube3a tm1Alb mice and wild-type (WT) littermates; ≥10 mice/group) were randomly assigned to standard housing (SH) or EE at weaning. EE had a larger footprint, a running wheel, and a variety of toys that promoted foraging, burrowing, and climbing. Following 6 weeks of EE, animals were submitted to a battery of tests that reliably elicit behavioral deficits in AS mice, including rotarod, open field, marble burying, and forced swim; weights were also monitored. Results:In male AS-EE mice, we found complete restoration of motor coordination, marble burying, and forced swim behavior to the level of WT-SH mice. We also observed a complete normalization of exploratory distance traveled in the open field, but we found no rescue of vertical behavior or center time. AS-EE mice also had weights comparable to WT-SH mice. Intriguingly, in the female AS-EE mice, we found a failure of EE to rescue the same behavioral deficits relative to female WT-SH mice.Conclusions: Environmental enrichment is an effective route to correcting the most penetrant phenotypes in male AS mice but not female AS mice. This finding has important implications for the translatability of early behavioral intervention for AS patients, most importantly the potential dependency of treatment response on sex.

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Environmental enrichment has minimal effects on behavior in the Shank3 complete knockout model of autism spectrum disorder

Cited by 18 publications

References 47 publications

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

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

Rho GTPases in the Amygdala—A Switch for Fears?

Sex‐dependent influence of postweaning environmental enrichment in Angelman syndrome model mice

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