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Cited by 38Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchAutism Spectrum Disorder Research

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

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Eltokhi, Ahmed, Gonzalez-Lozano, Miguel A., Oettl, Lars-Lennart, Rozov, Andrey, Pitzer, Claudia, Röth, Ralph, Berkel, Simone, Hüser, Markus +5 more·2021·Molecular Psychiatry
DOI 10.1038/s41380-021-01140-yPMC PMC8760046
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Abstract

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 Ca 2+-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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  • Disruption of SHANK family proteins alters PSD architecture, receptor localization, and subsequent signaling, leading to impaired synaptic transmission and plasticity that recapitulates autism-related phenotypes in animal models.

    “Disruption of SHANK family proteins alters PSD architecture, receptor localization, and subsequent signaling (Bucher et al., 2021), leading to impaired synaptic transmission and plasticity that recapitulates autism-related phenotypes in animal models (Eltokhi et al., 2021; Jung and Park, 2022).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Eltokhi et al., 2021

    The Abstract reports altered glutamatergic transmission in Shank knockout mice and, in this study, impaired synaptic plasticity and ASD-like behavior after SHANK2A overexpression. The Discussion also reports reduced synaptic transmission with SHANK3 mutations. These passages support the cited clause’s findings in animal models, but they do not establish that impaired transmission or plasticity caused the behavioral phenotypes. (LLM, conf=0.82)

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Authors
Eltokhi, A., Gonzalez-Lozano, M. A., Oettl, L.-L., Rozov, A., Pitzer, C., Röth, R., Berkel, S., Hüser, M., Harten, A., Kelsch, W., Smit, A. B., Rappold, G. A., & Sprengel, R.
Affiliations
  • Heidelberg University (DE)
  • Johannes Gutenberg University Mainz (DE)
  • Amsterdam Neuroscience (NL)
Corresponding author
  • Rappold, Gudrun A.
  • Sprengel, Rolf
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-05-21
Volume
26
Issue
11
Pages
6482-6504
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-021-01140-y
PMC
PMC8760046
OpenAlex
W3160147095
Cited by
38
References
11
Citations by year
2026: 7 · 2025: 9 · 2024: 7 · 2023: 2 · 2022: 8 · 2021: 5
FWCI
3.11
Type
journal article
Language
en
Update notices
correction (2021-07-08)
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
  • VU Research Portal (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
Ingeborg Ständer-Stiftung
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
Shank2, presynaptic function, postsynaptic function, autism spectrum disorder, social behavior, synaptic plasticity, olfactory cortex, olfactory processing, attention deficit hyperactivity disorder, neuropsychiatric disorders, developmental regulation
MeSH terms
Autism Spectrum Disorder, Animals, Hippocampus, Nerve Tissue Proteins, Neurons, Social Behavior, Receptors, AMPA, Mice

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