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PMID:20418887

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Citation

Shmelkov, SV, Hormigo, A, Jing, D, Proenca, CC, Bath, KG, Milde, T, Shmelkov, E, Kushner, JS, Baljevic, M, Dincheva, I, Murphy, AJ, Valenzuela, DM, Gale, NW, Yancopoulos, GD, Ninan, I, Lee, FS and Rafii, S (2010) Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nat. Med. 16:598-602, 1p following 602

Abstract

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.

Links

PubMed PMC2907076 Online version:10.1038/nm.2125

Keywords

Animals; Behavior, Animal; Compulsive Behavior/genetics; Grooming; Membrane Proteins/deficiency; Membrane Proteins/genetics; Mice; Mice, Knockout; Neostriatum/physiopathology; Nerve Tissue Proteins/deficiency; Nerve Tissue Proteins/genetics; Obsessive-Compulsive Disorder/diagnosis; Synapses; Synaptic Transmission

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GRIA1

located_in

GO:0008021: synaptic vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17549)

Seeded From UniProt

complete

MOUSE:GRIA2

located_in

GO:0008021: synaptic vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17549)

Seeded From UniProt

complete

MOUSE:NMDE1

located_in

GO:0008021: synaptic vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17549)

Seeded From UniProt

complete

MOUSE:NMDE2

located_in

GO:0008021: synaptic vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17549)

Seeded From UniProt

complete

MOUSE:SLIK5

acts_upstream_of_or_within

GO:0030534: adult behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4459459

P

Seeded From UniProt

complete

MOUSE:SLIK5

acts_upstream_of_or_within

GO:0021756: striatum development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4459459

P

Seeded From UniProt

complete

MOUSE:SLIK5

acts_upstream_of_or_within

GO:0007625: grooming behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4459459

P

Seeded From UniProt

complete

MOUSE:SLIK5

acts_upstream_of_or_within

GO:0007268: chemical synaptic transmission

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4459459

P

Seeded From UniProt

complete

MOUSE:SLIK5

acts_upstream_of_or_within

GO:0009410: response to xenobiotic stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4459459

P

Seeded From UniProt

complete

MOUSE:SLIK5

acts_upstream_of_or_within

GO:0048813: dendrite morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4459459

P

Seeded From UniProt

complete

MOUSE:SLIK5

acts_upstream_of_or_within

GO:0043588: skin development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4459459

P

Seeded From UniProt

complete

MOUSE:SLIK5

acts_upstream_of_or_within

GO:0072359: circulatory system development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4459459

P

Seeded From UniProt

complete

MOUSE:RFOX3

located_in

GO:0043025: neuronal cell body

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NMDE1

part_of

GO:0008021: synaptic vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(EMAPA:17549)

Seeded From UniProt

complete

MOUSE:NMDE2

part_of

GO:0008021: synaptic vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(EMAPA:17549)

Seeded From UniProt

complete

MOUSE:GRIA1

part_of

GO:0008021: synaptic vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(EMAPA:17549)

Seeded From UniProt

complete

See also

References

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