title: OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency.
abstract: Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.
authors.affiliation: Institute of Physiology I, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ullrich
authors.affiliation: Institute of Physiology II, University of Frankfurt, Frankfurt am Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weber
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University of Frankfurt, Frankfurt am Main, Germany.|Division of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition, Laboratory of Translational Neuroscience, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Post
authors.affiliation: Division of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition, Laboratory of Translational Neuroscience, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Popp
authors.affiliation: Institute of Physiology I, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Grein
authors.affiliation: Institute of Physiology I, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Zechner
authors.affiliation: Institute of Physiology I, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Guerrero González
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kreis
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: A G
authors.initials: AG
authors.lastname: Schmitt
authors.affiliation: Department of Neurology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Üçeyler
authors.affiliation: Division of Molecular Psychiatry, Clinical Research Unit on Disorders of Neurodevelopment and Cognition, Laboratory of Translational Neuroscience, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.|Department of Translational Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands.
authors.forename: K-P
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Institute of Physiology I, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: K
authors.identifier: 0000-0003-4475-0412
authors.initials: K
authors.lastname: Schuh
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D003192:Compulsive Behavior / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005473:Fluoxetine / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009770:Obsessive Behavior / Q000503:physiopathology; D009771:Obsessive-Compulsive Disorder / Q000378:metabolism* / Q000473:pathology*; D020813:Receptor, trkB / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D013788:Thalamus / Q000378:metabolism
chemical_list: D012097:Repressor Proteins; C433764:Spred2 protein, mouse; D005473:Fluoxetine; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases