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

Lee, Yong Seok; Yu, Nam Kyung; Chun, Jeewan; Yang, Jung Eun; Lim, Chae Seok; Kim, Hyopil; Park, Gaeun; Lee, Jin A; Lee, Kyung-Min; Kaang, Bong Kiun; Lee, Jae Hyung

doi:10.1186/s13041-020-00595-4

Cited by 11 publications

(8 citation statements)

References 32 publications

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“…Therefore, the simple suggestion of a hypomorphic SHANK does not explain the highly variable phenotypes in Shank KO mice and patients with SHANK mutations. Other putative SHANK isoforms may still be present and could play additional roles, which may have obscured the detailed functional analysis of SHANK and masked specific phenotypes in Shank KO mouse models [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

et al. 2021

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Mutations in SHANK genes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported in Shank KO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK proteins, but these remain poorly defined. In this study, we examined how SHANK2 can mediate electrophysiological, molecular, and behavioral effects by conditionally overexpressing either wild-type SHANK2A or the extrasynaptic SHANK2A(R462X) variant. SHANK2A overexpression affected pre- and postsynaptic targets and revealed a reversible, development-dependent autism spectrum disorder-like behavior. SHANK2A also mediated redistribution of Ca2+-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, leading to impaired synaptic plasticity in the basal dendrites. Moreover, SHANK2A overexpression reduced social interaction and increased the excitatory noise in the olfactory cortex during odor processing. In contrast, overexpression of the extrasynaptic SHANK2A(R462X) variant did not impair hippocampal synaptic plasticity, but still altered the expression of presynaptic/axonal signaling proteins. We also observed an attention-deficit/hyperactivity-like behavior and improved social interaction along with enhanced signal-to-noise ratio in cortical odor processing. Our results suggest that the disruption of pre- and postsynaptic SHANK2 functions caused by SHANK2 mutations has a strong impact on social behavior. These findings indicate that pre- and postsynaptic SHANK2 actions cooperate for normal neuronal function, and that an imbalance between these functions may lead to different neuropsychiatric disorders.

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Section: Introductionmentioning

confidence: 99%

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

et al. 2021

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“…In Shank2 mutant mouse models, anxiety-like behavior, hyperactivity, abnormal social behavior and dysregulation of synaptic molecules have been observed in specific regions of the brain [30].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel SHANK2 Pathogenic Variant in a Patient with a Neurodevelopmental Disorder

Doddato

Fabbiani

Scandurra

et al. 2022

Genes

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Genetic defects in the SHANK2 gene, encoding for synaptic scaffolding protein, are associated with a variety of neurodevelopmental conditions, including autism spectrum disorders and mild to moderate intellectual disability. Until now, limited patient clinical descriptions have been published. Only 13 unrelated patients with SHANK2 pathogenic variations or microdeletions have been reported worldwide. By Exome Sequencing, we identified a de novo stop-gain variant, c.334C>T, p.(Gln112*), in an Italian patient with a neurodevelopmental disorder. The patient (9 years old) presented the following facial features: a flat profile, thick eyebrows, long eyelashes, a bulbous nasal tip and a prominent columella, retracted ears, dental anomalies. The patient showed speech delay and mild neuromotor delay but not autism spectrum disorder. In conclusion, this patient with a novel pathogenic variant in SHANK2 enlarges the phenotypic spectrum of SHANK2-mutated patients and demonstrates that the severity of SHANK2-associated disorders is highly variable.

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“…A novel Shank2 transcriptional variant in a Shank2 deficient mouse model of ASD has shown that two lines of Shank2 knockout mice generated by deleting different exons (exon 6-7 or exon 7) showed distinct cellular phenotypes. Lee et al [7] also found expression of a novel exon (exon 4 ′ or e4') between the existing exons 4 and 5 in the Shank2 model of e6-7 Shank2 knockout mice. The results suggested an example of genetic indemnity, leading to phenotypic heterogeneity among ASD patients with the same gene mutation.…”

Section: Shank Family Of Genesmentioning

confidence: 94%

“…Moreover, it has recently been demonstrated that altered expression of specific genes are involved in processes of neurite elongation and synapse formation in the early developmental periods of MAGE Family Member L2 (Magel2)-deficient mice [5], which is another model known for the presence of autismlike symptoms. Currently, it appears that crucial factors that play a role in the pathogenesis of autism are defects and abnormalities found in postsynaptic density proteins [6][7][8]. Alterations for a wide range of postsynaptic density molecules and scaffolding proteins are currently being investigated at the molecular and cellular level in the context of neurodevelopmental disorders, with membrane-associated guanylate kinases representing the largest group amongst them [9].…”

Section: Introductionmentioning

confidence: 99%

The role of selected postsynaptic scaffolding proteins at glutamatergic synapses in autism-related animal models

Meliskova¹,

Havránek²,

Bačová³

et al. 2021

Journal of Integrative Neuroscience

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Pathological changes in synapse formation, plasticity and development are caused by altered trafficking and assembly of postsynaptic scaffolding proteins at sites of glutamatergic and gammaaminobutyric acid synapses, suggesting their involvement in the etiology of neurodevelopmental disorders, including autism. Several autism-related mouse models have been developed in recent years for studying molecular, cellular and behavioural defects to understand the etiology of autism and test potential treatment strategies. In this review, the role of alterations in selected postsynaptic scaffolding proteins in relevant transgene autism-like mouse models is explained. A summary is also provided of selected animal models by paying special attention to interactions between guanylate kinases or membrane-associated guanylate kinases, as well as other synapse protein components which form functional synaptic networks. The study of early developmental stages of autism-relevant animal models help in the understanding the origin and development of diverse autistic symptomatology.

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

Cited by 11 publications

References 32 publications

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

Identification of a Novel SHANK2 Pathogenic Variant in a Patient with a Neurodevelopmental Disorder

The role of selected postsynaptic scaffolding proteins at glutamatergic synapses in autism-related animal models

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