Enhancing inhibitory synaptic function reverses spatial memory deficits in Shank2 mutant mice

Lim, Chae Seok; Kim, Hyopil; Yu, Nam Kyung; Kang, Sukjae Joshua; Kim, Tae Hyun; Ko, Hyoung‐Gon; Lee, Jae-Hyun; Yang, Jung Eun; Ryu, Hwa-Sung; Park, Taesung; Gim, Jungsoo; Nam, Hye Jin; Baek, Sung Hee; Wegener, Stephanie; Schmitz, Dietmar; Boeckers, Tobias M.; Lee, Min Goo; Kim, Eunjoon; Lee, Jae Hyung; Lee, Yong Seok; Kaang, Bong Kiun

doi:10.1016/j.neuropharm.2016.08.016

Cited by 54 publications

(52 citation statements)

References 54 publications

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“…As the core proteins of the postsynaptic signaling pathway, Shanks play indispensable roles in the formation and regulation of postsynaptic densities . Human genetic studies demonstrated that the Shank gene family was the causative agent of ASD, and neurobiological studies of mouse Shank mutants suggested the hypothesis that ASD resulted from synaptic dysfunction . Sala et al confirmed that an increase in the Shank level might lead to postsynaptic precocity and an increase in the dendrite ridge volume.…”

Section: Discussionmentioning

confidence: 99%

Effect of the autism‐associated lncRNA Shank2‐AS on architecture and growth of neurons

Luo

Liu

Wang

et al. 2018

J of Cellular Biochemistry

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The pathogenic mechanism of autism is complex, and current research has shown that long noncoding RNAs (lncRNAs) may play important roles in this process. The antisense lncRNA of SH3 and multiple ankyrin repeat domains 2 (Shank2-AS) is upregulated in patients with autism spectrum disorder (ASD), whereas the expression of its sense strand gene Shank2 is downregulated. In neuronal cells, Shank2-AS and Shank2 can form a double-stranded RNA and inhibit Shank2 expression. Overexpression of Shank2-AS decreases neurite numbers and lengths, thereby inhibiting the proliferation of neuronal cells and promoting their apoptosis. Overexpression of Shank2 inhibits the abovementioned effects of Shank2-AS, and transfection of a vector containing the 10th intron of Shank2 (Shank2-AS is reverse-transcribed from this region) also blocks the function of Shank2-AS. Shank2 small interfering RNA plays a role similar to Shank2-AS. Therefore, Shank2-AS is abnormally expressed in patients with ASD and may affect the structure and growth of neurons by regulating Shank2 expression, thereby facilitating the development of ASD.

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Section: Discussionmentioning

confidence: 99%

Effect of the autism‐associated lncRNA Shank2‐AS on architecture and growth of neurons

Luo

Liu

Wang

et al. 2018

J of Cellular Biochemistry

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“…Deletions, duplications, and coding mutations in SHANK have been found in patients with ASD [Durand et al, ; Gauthier et al, ; Moessner et al, ; Phelan & McDermid, ; Pinto et al, ; Sanders et al, ; Sato et al, ; Soorya et al, ]. Furthermore, animal experiments showed that Shank1 ‐deficient mice display anxiety‐related behaviors, dysfunctions in vocal communication, locomotion, and long‐term memory [Hung et al, ; Wohr, Roullet, Hung, Sheng, & Crawley, ]; mice lacking Shank2 display hyperactivity, anxiety, repetitive behaviors, and impairments in vocal and social interaction [Lim et al, ; Schmeisser et al, ]; and behaviors displayed by mice with mutations in Shank3 are similar to those exhibited by mice lacking Shank2 or Shank1 [Jaramillo et al, ; Mei et al, ; Peca et al, ]. We further investigated associations between SNPs in SHANK family and ASD in northeast Chinese Han population, identifying that rs76717360 in SHANK2 is associated with increased ASD risk [Bai et al, ], and no significant SNPs in SHANK3 exist [Qiu et al, ].…”

Section: Introductionmentioning

confidence: 99%

SHANK1 polymorphisms and SNP–SNP interactions among SHANK family: A possible cue for recognition to autism spectrum disorder in infant age

Qiu

Bai

et al. 2019

Autism Research

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Autism spectrum disorder (ASD) is a serious lifelong neurodevelopmental disorder. ASD is diagnosed for children at the age of two. ASD diagnosis, as early as possible, lays the foundation for treatment and much better prognosis. Notably, gene‐based test is an inherent method to recognize the potential infants with ASD before the age of two. To investigate whether SHANK family contributes to ASD prediction, on the basis of our previous studies of SHANK2 and SHANK3, we further investigated associations between SHANK1 polymorphisms and ASD risk as well as SNP–SNP interactions among SHANK family. We enrolled 470 subjects (229 cases and 241 healthy controls) who were northeast Chinese Han. Four tag SNPs (rs73042561, rs3745521, rs4801846, and rs12461427) of SHANK1 were selected and genotyped. We used the SNPStats online analysis program to assess the associations between the four SNPs and ASD risk. The SNP–SNP interactions among SHANK family were analyzed using multifactor dimensionality reduction method. We found that the four SHANK1 SNPs were not associated with ASD risk in northeast Chinese Han population. There existed a strong synergistic interaction between rs11236697 [SHANK2] and rs74336682 [SHANK2], and moderate synergistic interactions (rs74336682 [SHANK2]–rs73042561 [SHANK1], rs11236697 [SHANK2]–rs77716438 [SHANK2], and rs11236697 [SHANK2]–rs75357229 [SHANK2]). These SHANK1 variants may not affect the susceptibility to ASD in Chinese Han population. SNP–SNP interactions in SHANK family may confer ASD risk. Autism Res 2019, 12: 375–383 © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary ASD is a serious lifelong neurodevelopmental disorder with strong genetic components. We investigated associations between SHANK1 polymorphisms and ASD risk as well as SNP–SNP interactions among SHANK family. Our results indicated that there exists no association between SHANK1 SNPs and ASD, and SNP–SNP interactions in SHANK family may confer ASD risk in the Northeast Han Chinese population. Future studies are needed to test more SHANK family SNPs in a large sample to demonstrate the associations.

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“…Interestingly, Shank2 KO mice lacking exons 6 and 7 (Shank2 e6-7 KO) showed hypo-function of N-methyl-D-aspartate receptor (NMDAR) and impaired long-term potentiation (LTP), whereas the other Shank2 mutant lacking exon 7 of the Shank2 gene (e7 KO) showed hyper-function of NMDAR and enhanced LTP in the adult hippocampus [10,11]. Recent studies showed that differences in gene expressions, experimental conditions, genetic background, and the developmental stages of the mice may, at least partially, explain the opposite cellular phenotypes in the two Shank2 mutant mouse models [13][14][15]. We have previously compared the gene expression profiles of Shank2 e6-7 and e7 KO mice by performing RNA-seq analyses, and found that the two KO mouse lines share only a few differentially expressed genes [14].…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies showed that differences in gene expressions, experimental conditions, genetic background, and the developmental stages of the mice may, at least partially, explain the opposite cellular phenotypes in the two Shank2 mutant mouse models [13][14][15]. We have previously compared the gene expression profiles of Shank2 e6-7 and e7 KO mice by performing RNA-seq analyses, and found that the two KO mouse lines share only a few differentially expressed genes [14]. In this study, we analyzed RNA-seq data from the hippocampi of two Shank2 mutant mouse models (e7 and e6-7 KO), and found a novel transcript that encodes a new exon in e6-7 and e7 KO mice.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel Shank2 transcriptional variant in Shank2 knockout mouse model of autism spectrum disorder

Lee

Chun

et al. 2020

Mol Brain

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Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that are highly heterogeneous in clinical symptoms as well as etiologies. Mutations in SHANK2 are associated with ASD and accordingly, Shank2 knockout mouse shows ASD-like behavioral phenotypes, including social deficits. Intriguingly, two lines of Shank2 knockout (KO) mouse generated by deleting different exons (exon 6-7 or exon 7) showed distinct cellular phenotypes. Previously, we compared gene expressions between Shank2 KOs lacking exon 6-7 (e6-7 KO) and KOs lacking exon 7 (e7 KO) by performing RNA-seq. In this study, we expanded transcriptomic analyses to identify novel transcriptional variants in the KO mice. We found prominent expression of a novel exon (exon 4′ or e4') between the existing exons 4 and 5 in the Shank2 e6-7 KO model. Expression of the transcriptional variant harboring this novel exon was confirmed by RT-PCR and western blotting. These findings suggest that the novel variant may function as a modifier gene, which contributes to the differences between the two Shank2 mutant lines. Furthermore, our result further represents an example of genetic compensation that may lead to phenotypic heterogeneity among ASD patients with mutations in the same gene.

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Enhancing inhibitory synaptic function reverses spatial memory deficits in Shank2 mutant mice

Cited by 54 publications

References 54 publications

Effect of the autism‐associated lncRNA Shank2‐AS on architecture and growth of neurons

Effect of the autism‐associated lncRNA Shank2‐AS on architecture and growth of neurons

SHANK1 polymorphisms and SNP–SNP interactions among SHANK family: A possible cue for recognition to autism spectrum disorder in infant age

Identification of a novel Shank2 transcriptional variant in Shank2 knockout mouse model of autism spectrum disorder

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