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Restoring striatal WAVE-1 improves maze exploration performance of GluN1 knockdown mice

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Chen, Yuxiao, Milenkovic, Marija, Horsfall, Wendy, Salahpour, Ali, Soderling, Scott H., Ramsey, Amy J.·2018·PLOS ONE
DOI 10.1371/journal.pone.0199341PMC PMC6198945

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Abstract

NMDA receptors are important for cognition and are implicated in neuropsychiatric disorders. GluN1 knockdown (GluN1KD) mice have reduced NMDA receptor levels, striatal spine density deficits, and cognitive impairments. However, how NMDA depletion leads to these effects is unclear. Since Rho GTPases are known to regulate spine density and cognition, we examined the levels of RhoA, Rac1, and Cdc42 signaling proteins. Striatal Rac1-pathway components are reduced in GluN1KD mice, with Rac1 and WAVE-1 deficits at 6 and 12 weeks of age. Concurrently, medium spiny neuron (MSN) spine density deficits are present in mice at these ages. To determine whether WAVE-1 deficits were causal or compensatory in relation to these phenotypes, we intercrossed GluN1KD mice with WAVE-1 overexpressing (WAVE-Tg) mice to restore WAVE-1 levels. GluN1KD-WAVE-Tg hybrids showed rescue of striatal WAVE-1 protein levels and MSN spine density, as well as selective behavioral rescue in the Y-maze and 8-arm radial maze tests. GluN1KD-WAVE-Tg mice expressed normalized WAVE-1 protein levels in the hippocampus, yet spine density of hippocampal CA1 pyramidal neurons was not significantly altered. Our data suggest a nuanced role for WAVE-1 effects on cognition and a delineation of specific cognitive domains served by the striatum. Rescue of striatal WAVE-1 and MSN spine density may be significant for goal-directed exploration and associated long-term memory in mice.

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  • A cross of GluN1KD mice with WAVE1-overexpressing mice rescued striatal WAVE1 protein levels and the MSN spine density, as well as behaviors in the Y-maze and 8-arm radial maze tests.

    “A cross of GluN1KD mice with WAVE1-overexpressing mice rescued striatal WAVE1 protein levels and the MSN spine density, as well as behaviors in the Y-maze and 8-arm radial maze tests62.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [62]

    The Results report that intercrossing restored striatal WAVE-1 levels, increased MSN spine density, and improved Y-maze performance. The 8-arm radial maze result was narrower: working-memory errors improved only partially, while the other reported measure remained impaired. Describing the maze behaviors as rescued without that qualification overstates the finding. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • GluN1 knockdown mice have reduced NMDA receptor levels, striatal spine density deficits, and cognitive impairments.

    “GluN1 knockdown (GluN1KD) mice have reduced NMDA receptor levels, striatal spine density deficits, and cognitive impairments.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [62]

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Cited by

Sorted by citations

Authors
Chen, Y., Milenkovic, M., Horsfall, W., Salahpour, A., Soderling, S. H., & Ramsey, A. J.
Affiliations
  • University of Toronto (CA)
  • Duke Medical Center (US)
Corresponding author
Ramsey, Amy J.
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2018-10-23
Volume
13
Issue
10
Pages
e0199341
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0199341
PMC
PMC6198945
OpenAlex
W2950120388
Cited by
5
References
8
Citations by year
2025: 2 · 2024: 1 · 2022: 1 · 2018: 1
FWCI
0.11
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • OSF Preprints (OSF Preprints) (submittedVersion)
Funders
  • Natural Sciences and Engineering Research Council of Canada (RGPIN-2018-06409)
  • National Institutes of Health (NIH R01 MH103374)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
NMDA receptor, striatum, medium spiny neurons, dendritic spine density, Rho GTPases, Rac1 signaling, cognitive impairment, spatial learning and memory, Y-maze, radial maze, hippocampus, gene rescue
MeSH terms
Animals, Behavior, Animal, Cognition, Crosses, Genetic, Exploratory Behavior, Female, Hippocampus, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Neuropeptides, Phenotype, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Mice, Knockout, Maze Learning, Transgenes, rho GTP-Binding Proteins, rac1 GTP-Binding Protein, Dendritic Spines, Wiskott-Aldrich Syndrome Protein Family, Mice

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