Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP

Muhia, Mary; Yee, Benjamin K.; Feldon, Joram; Markopoulos, Foivos; Knuesel, Irene

doi:10.1111/j.1460-9568.2010.07079.x

Cited by 71Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchNeurogenesis and neuroplasticity mechanisms

Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP

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Muhia, Mary, Yee, Benjamin K., Feldon, Joram, Markopoulos, Foivos, Knuesel, Irene·2010·European Journal of Neuroscience

DOI 10.1111/j.1460-9568.2010.07079.x

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Abstract

The brain‐specific Ras/Rap‐GTPase activating protein (SynGAP) is a prime candidate linking N‐methyl‐d‐aspartate receptors to the regulation of the ERK/MAP kinase signalling cascade, suggested to be essential for experience‐dependent synaptic plasticity. Here, we evaluated the behavioural phenotype of SynGAP heterozygous knockout mice (SG+/−), expressing roughly half the normal levels of SynGAP. In the cognitive domain, SG+/− mice demonstrated severe working and reference memory deficits in the radial arm maze task, a mild impairment early in the transfer test of the water maze task, and a deficiency in spontaneous alternation in an elevated T‐maze. In the non‐cognitive domain, SG+/− mice were hyperactive in the open field and appeared less anxious in the elevated plus maze test. In contrast, object recognition memory performance was not impaired in SG+/− mice. The reduction in SynGAP thus resulted in multiple behavioural traits suggestive of aberrant cognitive and non‐cognitive processes normally mediated by the hippocampus. Immunohistochemical evaluation further revealed a significant reduction in calbindin‐positive interneurons in the hippocampus and doublecortin‐positive neurons in the dentate gyrus of adult SG+/− mice. Heterozygous constitutive deletion of SynGAP is therefore associated with notable behavioural as well as morphological phenotypes indicative of hippocampal dysfunction. Any suggestion of a possible causal link between them however remains a matter for further investigation.

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Adult SynGAP heterozygous knockout mice have profound cognitive abnormalities despite lack of pervasive functional synaptic defects.
“Despite the lack of pervasive functional synaptic defects in adulthood, these animals have profound cognitive abnormalities”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Muhia et al., 2010

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Authors: Muhia, M., Yee, B. K., Feldon, J., Markopoulos, F., & Knuesel, I.
Affiliations: Harvard University (US)
ORCID: Muhia, Mary
Yee, Benjamin K.
Markopoulos, Foivos
Venue: European Journal of Neuroscience
Publisher: Wiley
Published: 2010-02
Volume: 31
Issue: 3
Pages: 529-543
ISSN: 0953-816X (ISSN-L)
1460-9568
DOI: 10.1111/j.1460-9568.2010.07079.x
OpenAlex: W1994193742
Cited by: 71
References: 101
Citations by year: 2026: 3 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 8 · 2019: 7 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 4 · 2014: 4 · 2013: 5 · 2012: 7
FWCI: 3.49
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: European Journal of Neuroscience (publishedVersion)
PubMed (publishedVersion)
Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
Zurich Open Repository and Archive (University of Zurich)
Funders: California Institute of Technology
Eidgenössische Technische Hochschule Zürich
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords: SynGAP, heterozygous knockout mice, hippocampus, working memory, reference memory, spatial memory, anxiety, hyperactivity, doublecortin, dentate gyrus, NMDA receptor, synaptic plasticity, behavioral phenotypes
MeSH terms: Animals, Behavior, Animal, Female, Hippocampus, Male, Memory, Neurons, Neuropsychological Tests, Mice, Knockout, Maze Learning, ras GTPase-Activating Proteins, Mice

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Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP

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