Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice
Open accessAbstract
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms. Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD. However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component. Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5(-/-) mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.
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Three animal models exhibit markedly elevated grooming: the HoxB8 knockout mouse, the SAPAP3 knockout mouse, and the SliTrk5 knockout mouse.
“Three models in particular exhibit markedly elevated grooming: the HoxB8 knockout mouse,[20] the SAPAP3 knockout mouse,[21] and the SliTrk5 knockout mouse.[22]”
From Trichotillomania (hair pulling disorder) (2019) · cites this paper as [22]
Slitrk5 knockout mice have OFC overactivation as measured with baseline c-fos staining, paralleling findings from human neuroimaging studies.
“Slitrk5 KOs also have OFC overactivation as measured with baseline c-fos staining, paralleling findings from human neuroimaging studies.”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [93]
Slitrk5 knockout mice demonstrate increased anxiety and perseverative grooming that are reversed by chronic fluoxetine treatment.
“Slitrk5 KOs demonstrate increased anxiety and perseverative grooming that are reversed by chronic treatment with fluoxetine, demonstrating relevance to human OCD.”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [93]
Cortico-striatal circuitry dysfunction has been strongly implicated in repetitive/compulsive behaviours in OCD.
“Cortico-striatal circuitry dysfunction has also been strongly implicated in repetitive/compulsive behaviours in OCD31–33.”
From Shank3 mutant mice display autistic-like behaviours and striatal dysfunction (2011) · cites this paper as [32]
Genetic deletion of Slitrk5 in mice results in excessive grooming associated with facial hair loss and skin lesions and with impaired corticostriatal neurotransmission.
“Genetic deletion of Slitrk5 in mice also results in excessive grooming associated with facial hair loss and skin lesions and with impaired corticostriatal neurotransmission [510].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [510]
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“Three models in particular exhibit markedly elevated grooming: the HoxB8 knockout mouse,[20] the SAPAP3 knockout mouse,[21] and the SliTrk5 knockout mouse.[22] The potential relevance of SAPAP3, in particular, to trichotillomania, is reinforced by the finding that rare variations in the SAPAP3 gene are associated with…”
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Retracted
- Authors
- Shmelkov, S. V., Hormigo, A., Jing, D., Proenca, C. C., Bath, K. G., Milde, T., Shmelkov, E., Kushner, J. S., Baljevic, M., Dincheva, I., Murphy, A. J., Valenzuela, D. M., Gale, N. W., Yancopoulos, G. D., Ninan, I., Lee, F. S., & Rafii, S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Weill Cornell Medicine (US)
- Regeneron (United States) (US)
- NYU Langone Health (US)
- Corresponding author
- Lee, Francis S
- Rafii, Shahin
- ORCID
- Venue
- Nature Medicine
- Published
- 2010-04-25
- Volume
- 16
- Issue
- 5
- Pages
- 598-602
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2907076
- OpenAlex
- W2014564921
- Cited by
- 361
- References
- 39
- Citations by year
- 2026: 18 · 2025: 18 · 2024: 23 · 2023: 22 · 2022: 19 · 2021: 23 · 2020: 20 · 2019: 25 · 2018: 21 · 2017: 25 · 2016: 22 · 2015: 33 · 2014: 19 · 2013: 24 · 2012: 18
- FWCI
- 24.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (HL-66592, R01HL097797, U01HL066952, HL097797)
- National Institute of Mental Health (P50MH079513, MH079513, RC1MH088814)
- National Institute of Allergy and Infectious Diseases (RC1AI080309, AI080309)
- National Institute of Neurological Disorders and Stroke (NS052819, R01NS052819)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- obsessive-compulsive disorder, corticostriatal circuits, self-grooming, anxiety-like behavior, fluoxetine, orbitofrontal cortex, glutamate receptors, transmembrane proteins, mouse model, gene knockout
- MeSH terms
- Animals, Behavior, Animal, Compulsive Behavior, Grooming, Membrane Proteins, Nerve Tissue Proteins, Synaptic Transmission, Obsessive-Compulsive Disorder, Synapses, Neostriatum, Mice, Knockout, Mice
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