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Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice.

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.

Pubmed ID: 20418887

Authors

  • 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
  • Rafii S

Journal

Nature medicine

Publication Data

May 7, 2010

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI080309
  • Agency: NHLBI NIH HHS, Id: HL097797
  • Agency: NHLBI NIH HHS, Id: HL66592
  • Agency: NIMH NIH HHS, Id: MH079513
  • Agency: NINDS NIH HHS, Id: NS052819
  • Agency: NHLBI NIH HHS, Id: R01 HL097797
  • Agency: NHLBI NIH HHS, Id: R01 HL097797-02
  • Agency: NINDS NIH HHS, Id: R01 NS052819
  • Agency: NINDS NIH HHS, Id: R01 NS052819-07
  • Agency: NIAID NIH HHS, Id: RC1 AI080309
  • Agency: NIAID NIH HHS, Id: RC1 AI080309-01
  • Agency: NIMH NIH HHS, Id: RC1 MH088814
  • Agency: NIMH NIH HHS, Id: RC1 MH088814-02
  • Agency: NHLBI NIH HHS, Id: U01 HL066952
  • Agency: NHLBI NIH HHS, Id: U01 HL066952-010002
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Behavior, Animal
  • Compulsive Behavior
  • Grooming
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Neostriatum
  • Nerve Tissue Proteins
  • Obsessive-Compulsive Disorder
  • Synapses
  • Synaptic Transmission