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.
Shmelkov
Sergey V
SV
[1] Howard Hughes Medical Institute, Ansary Stem Cell Institute and Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA. [2] These authors contributed equally to this work.
Hormigo
Adília
A
Jing
Deqiang
D
Proenca
Catia C
CC
Bath
Kevin G
KG
Milde
Till
T
Shmelkov
Evgeny
E
Kushner
Jared S
JS
Baljevic
Muhamed
M
Dincheva
Iva
I
Murphy
Andrew J
AJ
Valenzuela
David M
DM
Gale
Nicholas W
NW
Yancopoulos
George D
GD
Ninan
Ipe
I
Lee
Francis S
FS
Rafii
Shahin
S
D000818:Animals; D001522:Behavior, Animal; D003192:Compulsive Behavior / Q000235:genetics; D006120:Grooming; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017072:Neostriatum / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009771:Obsessive-Compulsive Disorder / Q000175:diagnosis*; D013569:Synapses; D009435:Synaptic Transmission
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C550141:Slitrk5 protein, mouse