Jenna Sturgeon

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that manifests as abnormal cognitive deficits including impaired executive dysfunction, atypical perception and information processing, altered social cognition and repetitive behaviors and interests.¹ ASD is influenced by both genetic mutations and environmental factors. ASD is known to co-occur with other conditions such as epilepsy, ADHD, depression, anxiety, self-harm and sleep challenges.¹ Diagnoses are made at the recognition of symptoms, which does not always correlate with the onset of the disease.¹ Although there is no cure for autism, there are interventions to improve function, skills and quality of life if diagnosed early.²

Objective: In this narrative review, we explored the significance of SHANK3 scaffolding protein in different animal models and how it relates to social behaviors.

Search Methods: An online search in the PubMed database was conducted from 2019 to 2024 using the following keywords: “autism spectrum disorder”, “SHANK3” , “Shank3 protein, rat”, with the Mesh term filters “genetics” and “microbiology”.

Results: SHANK3 is a key excitatory postsynaptic scaffold protein that plays an important role in regulating postsynaptic neurotransmitter receptors and signaling molecules, including glutamatergic synaptic development and function.^4,5 Previous mouse model studies demonstrated that the deletion of SHANK3 results in abnormal behaviors such as repetitive behavior and social interaction deficits, similar to those exhibited by human children with ASD.⁴ Experiments in the anterior cingulate cortex of the brain found that SHANK3 knockout mice had significantly lower dendritic complexity and density, and lower average length and thickness of postsynaptic densities, suggesting that the absence of SHANK3 leads to structural defects in ACC pyramidal neurons.⁴ Another study further explored GABAergic pyramidal neurons, and found that SHANK3 mice were more sensitive to weak vibrations and had increased spontaneous and stimulated activity in pyramidal neurons, but reduced activity in interneurons.⁵ These findings suggest that interneuron dysfunction in SHANK3 deficient mice may be linked to abnormal pyramidal neuron hyperexcitability and sensory hypersensitivity.⁵ A study done in canines found pyramidal neuron hyperexcitability, impaired synaptic transmission, and reduced dendrite elongation and spine density in SHANK3 mutant dogs.⁶ Another study tested SHANK3 mutant monkeys for social behaviors and eye movements.⁷ SHANK3 mutant monkeys displayed reduced socialization, vocalization, and levels of exploration compared to WT monkeys.⁷ When viewing paired still images of other monkey faces and objects, SHANK3 mutant monkeys spent less time overall fixated on the images and more time switching fixations compared to the WT monkeys.⁷

Conclusions: Studies have found that deficiency of the SHANK3 protein leads to manifestation of abnormal social behaviors and brain anatomy in rats and macaques, which suggests the sufficiency of using alternative animal models to rats in neurodevelopmental studies.^6,7 Additionally, restoration of the SHANK3 gene in deficient mice rescued abnormal social behaviors and restored brain activity, such as excitatory postsynaptic currents, to normal wild type levels.⁴ Using methods such as Whole Exome Sequencing to identify pathogenic genes could lead to early identification of autism spectrum disorder related genes and improve patient outcomes with early intervention.⁸

Work Cited:

1. Wang L, Wang B, Wu C, Wang J, Sun M. Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy. Int J Mol Sci. 2023;24(3):1819. Published 2023 Jan 17. doi:10.3390/ijms24031819
2. Hyman SL, Levy SE, Myers SM; COUNCIL ON CHILDREN WITH DISABILITIES, SECTION ON DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. 2020;145(1):e20193447. doi:10.1542/peds.2019-3447
3. Aishworiya R, Valica T, Hagerman R, Restrepo B. An Update on Psychopharmacological Treatment of Autism Spectrum Disorder. Neurotherapeutics. 2022;19(1):248-262. doi:10.1007/s13311-022-01183-1
4. Guo B, Chen J, Chen Q, et al. Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice. Nat Neurosci. 2019;22(8):1223-1234. doi:10.1038/s41593-019-0445-9
5. Chen Q, Deister CA, Gao X, et al. Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD. Nat Neurosci. 2020;23(4):520-532. doi:10.1038/s41593-020-0598-6
6. Zhu F, Shi Q, Jiang YH, Zhang YQ, Zhao H. Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs. Mol Autism. 2024;15(1):9. Published 2024 Jan 31. doi:10.1186/s13229-024-00587-4
7. Zhou Y, Sharma J, Ke Q, et al. Atypical behavior and connectivity in SHANK3-mutant macaques. Nature. 2019;570(7761):326-331. doi:10.1038/s41586-019-1278-0
8. Bruno LP, Doddato G, Valentino F, et al. New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing. Int J Mol Sci. 2021;22(24):13439. Published 2021 Dec 14. doi:10.3390/ijms222413439