Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

Abstract

Background Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. Main text This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Conclusions Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.

Deletion of the Autism-Associated Protein SHANK3 Abolishes Structural Synaptic Plasticity after Brain Trauma

“…In addition to this, the generation and analysis of mice lines lacking different SHANK3 isoforms have revealed insights into SHANK3 relevance at the synapses. At the morphological level, these animals showed reduced dendritic spine density with longer spines and no alterations in the PSD ultrastructure [ 9 ], while others exhibited reduced dendritic spine density and smaller PSD [ 10 , 11 ]. Furthermore, the PSDs of these animals are known to have fewer proteins responsible for local actin remodeling as well as other synaptic proteins, such as Homer [ 10 , 12 , 13 , 14 , 15 , 16 ].…”

Auditory Dysfunction in Animal Models of Autism Spectrum Disorder

“…The SHANK3 gene encodes a scaffold protein (SHANK3) enriched in the post-synaptic density of excitatory synapses and is currently one of the best characterized risk genes in ASD ( Monteiro and Feng, 2017 ). Several studies have shown that Shank3 mutations in zebrafish ( Liu et al, 2018 ), mice ( Mei et al, 2016 ; Zhou et al, 2016 ), rats ( Song et al, 2019 ), and even primates ( Zhou Y. et al, 2019 ), lead to reduced social interaction and repetitive behaviors, as well as other numerous defects ( Peça et al, 2011 ; Zhou et al, 2016 ; Delling and Boeckers, 2021 ).…”

SHANK3 Antibody Validation: Differential Performance in Western Blotting, Immunocyto- and Immunohistochemistry

“…Knock-down experiments in primary neurons ( Verpelli et al, 2011 ) and human-induced pluripotent stem cell–derived cells including enterocytes ( Pfaender et al, 2017 ), neurons ( Shcheglovitov et al, 2013 ; Lutz et al, 2020 ), and muscle cells ( Lutz et al, 2020 ) have been performed and various mouse models have been generated carrying different deletions and mutations of SHANK3 ( Jiang and Ehlers, 2013 ; Delling and Boeckers, 2021 ). Interestingly, these SHANK3-deficient mouse models manifest with different phenotypes dependent on the location of the deletion in Shank3 ( Delling and Boeckers, 2021 ). Dependent on multiple internal promotors, six different isoforms of SHANK3 are known, and with alternative splicing at least 10 SHANK3 isoforms can be generated ( Wang et al, 2014 ).…”