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Swimming exercise is a promising early intervention for autism-like behavior in Shank3 deletion rats.

ABSTRACT: SHANK3 is an important excitatory postsynaptic scaffold protein, and its mutations lead to genetic cause of neurodevelopmental diseases including autism spectrum disorders (ASD), Philan McDermid syndrome (PMS), and intellectual disability (ID). Early prevention and treatment are important for Shank3 gene mutation disease. Swimming has been proven to have a positive effect on neurodegenerative diseases. Shank3 gene exon 11-21 knockout rats were intervened by a 40 min/day, 5 day/week for 8-week protocol. After the intervention, the rats were tested to behavioral measures such as learning and memory, and the volume and H-spectrum of the brain were measured using MRI; hippocampal dendritic spines were measured using Golgi staining and laser confocal. The results showed that Shank3-deficient rats had significant deficits in social memory, object recognition, and water maze learning decreased hippocampal volume and number of neurons, and lower levels of related scaffold proteins and receptor proteins were found in Shank3-deficient rats. It is suggested that early swimming exercise has a positive effect on Shank3 gene-deficient rats, which provides a new therapeutic strategy for the prevention and recovery of neurodevelopmental disorders.

SUBMITTER: Xu D

PROVIDER: S-EPMC9804047 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Swimming exercise is a promising early intervention for autism-like behavior in Shank3 deletion rats.

Xu Dan D Meng Yunchen Y An Shasha S Meng Wenshu W Li Hanran H Zhang Weinan W Xue Yaqi Y Lan Xinyu X Wang Xiaoxi X Li Mingjuan M Zhang Xiaoyan X Zhihao Zhang Z Zhao Yu Y Yang Haodong H Zhang Chen C Zhang Rong R Zhen Zhiping Z

CNS neuroscience & therapeutics 20221011 1

<h4>Introduction</h4>SHANK3 is an important excitatory postsynaptic scaffold protein, and its mutations lead to genetic cause of neurodevelopmental diseases including autism spectrum disorders (ASD), Philan McDermid syndrome (PMS), and intellectual disability (ID). Early prevention and treatment are important for Shank3 gene mutation disease. Swimming has been proven to have a positive effect on neurodegenerative diseases.<h4>Methods</h4>Shank3 gene exon 11-21 knockout rats were intervened by a ...[more]

PMID: 36221783

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Project description:BackgroundPatients 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.MethodsWe 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.ResultsMale 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.LimitationsThis 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.ConclusionOur 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.

Project description:Background22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the syndrome.MethodsA serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G.ResultsThirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features.ConclusionsThis study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the prominence of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

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Swimming exercise is a promising early intervention for autism-like behavior in Shank3 deletion rats.

Publications

Swimming exercise is a promising early intervention for autism-like behavior in Shank3 deletion rats.

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