Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome

Lin, Raozhou; Learman, Lisa N.; Bangash, Muhammad; Melnikova, Tatiana; Leyder, Erica; Reddy, Sai C.; Naidoo, Nirinjini; Park, Joo Min; Savonenko, Alena; Worley, Paul F.

doi:10.1016/j.celrep.2021.110014

Cited by 9 publications

(10 citation statements)

References 54 publications

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“…Whether similar changes are seen in Shank3 WT/ΔC heterozygous mice exposed to ELSD will need to be determined. We speculate that Shank3 may be engaged in protective or homeostatic adaptations, as has been suggested by prior work [ 44 , 56 ], that mitigate the effects of ELSD treatment in WT mice, thus reduced Shank3 function results in vulnerability to sleep loss in Shank3 WT/ΔC heterozygotes.…”

Section: Discussionsupporting

confidence: 54%

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

et al. 2022

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Background Patients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3WT/ΔC mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption. Methods We recorded sleep behavior in developing Shank3ΔC/ΔC, Shank3WT/ΔC, and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3WT/ΔC and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults. Results Male and female Shank3ΔC/ΔC mice slept significantly less than wild-type and Shank3WT/ΔC siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3WT/ΔC mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3WT/ΔC subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3WT/ΔC subjects had a significant reduction in risk aversion. CON Shank3WT/ΔC mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests. Limitations This study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities. Conclusion Our study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility.

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Section: Discussionsupporting

confidence: 54%

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

et al. 2022

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“…As previously reported, under control conditions Shank3 WT/ΔC heterozygotes of both sexes showed intact sociability, comparable to WT littermates (Fig. 5A-C) (26, 44). In response to ELSD or PASD treatments, all groups showed intact sociability, with the clear exception of male ELSD- Shank3 WT/ΔC heterozygotes that exhibited a lack of preference for the social stimulus (S) in comparison to the non-social stimulus (N) (ELSD HET p = 0.125; ELSD WT p = 0.0006; CON HET p = 0.0384; CON WT p = 0.02, paired t-test with Holm-Šídák correction for all social behavior results) (Fig.…”

Section: Resultssupporting

confidence: 87%

“…Whether similar changes are seen in Shank3 WT/ΔC heterozygous mice exposed to ELSD will need to be determined. We speculate that Shank3 may be engaged in protective or homeostatic adaptations, as has been suggested by prior work (44, 56), that mitigate the effects of ELSD treatment in WT mice, thus reduced Shank3 function results in vulnerability to sleep loss in Shank3 WT/ΔC heterozygotes.…”

Section: Discussionsupporting

confidence: 55%

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

Lord

Harper²,

Nikolova³

et al. 2021

Preprint

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Sleep disruption is a common comorbidity in patients with autism spectrum disorder (ASD), a condition diagnosed with a striking male bias of ~4:1. It is unclear how sleep disruption contributes to ASD susceptibility, and the sex biased vulnerability. We examined sleep behavior and the effects of early life sleep disruption (ELSD) in developing mice bearing C-terminal truncation (ΔC) in ASD risk gene Shank3. Male and female Shank3ΔC/ΔC homozygotes showed clear sleep disruption early in postnatal life, compared to Shank3WT/ΔC heterozygotes and wild-type littermates, suggesting that sleep disruption may be an early symptom in the expression of ASD. We find that ELSD interacts with genetic vulnerability in Shank3WT/ΔC heterozygotes to drive lasting and sex-specific changes in behavior. Our results clearly show that sleep disruption during sensitive periods of postnatal development is causative of lasting changes in behavior in genetically vulnerable individuals, but in a striking sex-specific manner.

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“…Several lines of evidence demonstrate that Shank3 expression is regulated by Homer protein homolog 1a (Homer1a), which is part of the Shank3-mGluR-N-methyl-D-aspartate (NMDA) receptor complex and is super-induced and implicated in the stress response. The interaction between stress and genetics and focus attention on activity-dependent changes may contribute to pathogenesis [ 38 ].…”

Section: Etiopathogenesismentioning

confidence: 99%

“…More detailed information on developmental characteristics in children is clearly necessary for care and would contribute to improving counselling of parents, identification of specific problems, adequate and individualized support for the persons with PMS [ 38 ].…”

Section: Interdisciplinary Clinical Managementmentioning

confidence: 99%

Clinical and Genetic Aspects of Phelan–McDermid Syndrome: An Interdisciplinary Approach to Management

Scalisi

Callea

Martinelli

et al. 2022

Genes

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Phelan–McDermid syndrome (PMS) is a rare, heterogeneous, and complex neurodevelopmental disorder. It is generally caused by a heterozygous microdeletion of contiguous genes located in the distal portion of the long arm of chromosome 22, including the SHANK3 gene. Sequence variants of SHANK3, including frameshift, nonsense mutations, small indels and splice site mutations also result in PMS. Furthermore, haploinsufficiency in SHANK3 has been suggested as the main cause of PMS. SHANK3 is also associated with intellectual disability, autism spectrum disorder and schizophrenia. The phenotype of PMS is variable, and lacks a distinctive phenotypic characteristic, so the clinical diagnosis should be confirmed by genetic analysis. PMS is a multi-system disorder, and clinical care must encompass various specialties and therapists. The role of risperidone, intranasal insulin, insulin growth factor 1, and oxytocin as potential therapeutic options in PMS will be discussed in this review. The diagnosis of PMS is important to provide an appropriate clinical evaluation, treatment, and genetic counseling.

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Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome

Cited by 9 publications

References 54 publications

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

Clinical and Genetic Aspects of Phelan–McDermid Syndrome: An Interdisciplinary Approach to Management

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