SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

Malara, Mariagiovanna; Lutz, Anne-Kathrin; Incearap, Berra; Bauer, Helen Friedericke; Cursano, Silvia; Volbracht, Katrin; Lerner, Joanna Janina; Pandey, Rakshita; Delling, Jan Philipp; Ioannidis, Valentin; Arévalo, Andrea Pérez; Bernhardi, Jaime Eugenin von; Schön, Michael P.; Bockmann, Jürgen; Dimou, Leda; Boeckers, Tobias M.

doi:10.1007/s00018-022-04400-4

Cited by 26 publications

(11 citation statements)

References 76 publications

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“…Therefore, axonal, somatic, and nuclear expressions are described ( Beri et al, 2007 ; Wang et al, 2014 ). SHANK3 is also found in many non-neuronal tissues, including heart, liver, kidney, muscle, and myelinating cells ( Lim et al, 1999 ; Lutz et al, 2020 ; Malara et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders

Bauer

Delling²,

Bockmann³

et al. 2023

Front. Behav. Neurosci.

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Individuals with a SHANK3-related neurodevelopmental disorder, also termed Phelan-McDermid syndrome or abbreviated as PMS, exhibit significant global developmental delay, language impairment, and muscular hypotonia. Also common are repetitive behaviors and altered social interactions, in line with a diagnosis of autism spectrum disorders. This study investigated the developmental aspect of autism-related behaviors and other phenotypes in a Shank3-transgenic mouse model. The animals underwent two sets of identical behavioral experiments, spanning motor skills, social and repetitive behavior, and cognition: baseline began at 5 weeks of age, corresponding to human adolescence, and the follow-up was initiated when aged 13 weeks, resembling early adulthood in humans. Interestingly, the animals displayed relatively stable phenotypes. Moreover, motor coordination and endurance were impaired, while muscle strength was unchanged. Surprisingly, the animals displayed only minor impairments in social behavior, but pronounced stereotypic and repetitive behaviors. Some behavioral tests indicated increased avoidance and anxiety. While spatial learning and memory were unchanged, knockout animals displayed slightly impaired cognitive flexibility. Female animals had similar abnormalities as males in the paradigms testing avoidance, anxiety, and cognition, but were less pathological in motor function and repetitive behavior. In all test paradigms, heterozygous Shank3 knockout animals had either no abnormal or a milder phenotype. Accurate characterization of animal models for genetic diseases is a prerequisite for understanding the pathophysiology. This is subsequently the basis for finding suitable and, ideally, translational biomarkers for therapeutic approaches and, thereby reducing the number of animals needed for preclinical trials.

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Section: Introductionmentioning

confidence: 99%

Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders

Bauer

Delling²,

Bockmann³

et al. 2023

Front. Behav. Neurosci.

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“…(O.C.T. ), since the gelatin sticks well to the skin of the pup and therefore prevents the skin from separating from the rest of the tissue while cutting later for immunohistochemistry [ 10 ].…”

Section: Expected Resultsmentioning

confidence: 99%

Trans-cardiac perfusion of neonatal mice and immunofluorescence of the whole body as a method to study nervous system development

Arévalo

Lutz²,

Atanasova³

et al. 2022

PLoS ONE

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Whole animal perfusion is a well-established method that has been used for the past decades in multiple research fields. Particularly, it has been very important for the study of the brain. The rapid and uniform fixation of tissue is essential for the preservation of its integrity and the study of complex structures. For small tissue pieces submerging in formaldehyde solution oftentimes is sufficient to get a good fixation, larger tissues or organs with a more complicated structure present a greater difficulty. Here, we report the precise parameters to successfully perform trans-cardiac perfusion of neonatal mouse pups that allows a uniform fixation of the whole body for subsequent structural analysis and immunohistochemistry. In comparison to standard perfusion procedures of adult mice, changes in the pump velocity, the buffer volume and in the needle size lead to high quality fixation of neonatal mice pups. Further, we present a whole-body section staining, which results in a highly specific immunofluorescence signal suited for detailed analysis of multiple tissues or systems at the same time. Thus, our protocol provides a reproducible and reliable method for neonatal perfusion and staining that can rapidly be applied in any laboratory. It allows a high quality analysis of cellular structures and expression profiles at early developmental stages.

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“…As they still lack the major SHANK3 isoforms, it could be that the structure of the post-synapse is not optimal and does not permit normal functionality of the synapse and therefore this is the reason for the behavioral deficits. Even if in this study we looked into protein expression in distinct brain regions, neural circuit pathology has been found in Shank3 -deficient mice [ 69 , 70 ] and in offspring of poly I:C-injected dams [ 71 ]. In addition, the interaction between HOMER1 and mGluR5 has been found to be of crucial importance in cortico-striatal connectivity [ 72 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

Immune activation during pregnancy exacerbates ASD-related alterations in Shank3-deficient mice

et al. 2023

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Background Autism spectrum disorder (ASD) is mainly characterized by deficits in social interaction and communication and repetitive behaviors. Known causes of ASD are mutations of certain risk genes like the postsynaptic protein SHANK3 and environmental factors including prenatal infections. Methods To analyze the gene-environment interplay in ASD, we combined the Shank3Δ11−/− ASD mouse model with maternal immune activation (MIA) via an intraperitoneal injection of polyinosinic/polycytidylic acid (Poly I:C) on gestational day 12.5. The offspring of the injected dams was further analyzed for autistic-like behaviors and comorbidities followed by biochemical experiments with a focus on synaptic analysis. Results We show that the two-hit mice exhibit excessive grooming and deficits in social behavior more prominently than the Shank3Δ11−/− mice. Interestingly, these behavioral changes were accompanied by an unexpected upregulation of postsynaptic density (PSD) proteins at excitatory synapses in striatum, hippocampus and prefrontal cortex. Limitations We found several PSD proteins to be increased in the two-hit mice; however, we can only speculate about possible pathways behind the worsening of the autistic phenotype in those mice. Conclusions With this study, we demonstrate that there is an interplay between genetic susceptibility and environmental factors defining the severity of ASD symptoms. Moreover, we show that a general misbalance of PSD proteins at excitatory synapses is linked to ASD symptoms, making this two-hit model a promising tool for the investigation of the complex pathophysiology of neurodevelopmental disorders.

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SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

Cited by 26 publications

References 76 publications

Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders

Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders

Trans-cardiac perfusion of neonatal mice and immunofluorescence of the whole body as a method to study nervous system development

Immune activation during pregnancy exacerbates ASD-related alterations in Shank3-deficient mice

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