ArticleMolecular psychiatry2018
OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency.
Article in Molecular psychiatry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48 citing papers in PubMed, 85 citations in OpenAlex.
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- TRIM25 Suppresses Hippocampal Neuronal Autophagy under High Glucose via Ubiquitination and Degradation of SIX2.Journal of molecular neuroscience : MN · 2026Article
- Targeting tubular NAT10 ameliorates the renal Tubulointerstitial Fibrosis in Obstructive and Folic Acid-Induced Nephropathy.International journal of biological sciences · 2026Article
- Neural mechanisms underlying cognitive inflexibility in obsessive-compulsive disorder: a review.Frontiers in psychiatry · 2026Review
- Different Protocols of Circadian Rhythm Disruptions Differentially Affect Locomotor Activity, and Anxiety- and Compulsive-Like Behaviors in Male vs. Female Wistar Rats along with the Significant Involvement of GSK-3β in Females.Molecular neurobiology · 2025Article
- A Multi-omics Exploration Revealing SLIT2 as a Prime Therapeutic Target for Peripheral Facial Paralysis: Integrating Single-Cell Transcriptomics and Plasma Proteome Data.Cellular and molecular neurobiology · 2025Article
- Advancing Obsessive-Compulsive Disorder Research: Insights from Transgenic Animal Models and Innovative Therapies.Brain sciences · 2025Review
- Late development of OCD-like phenotypes in Dlgap1 knockout mice.Psychopharmacology · 2025Article
- Experimental and clinical tests of FDA-approved kinase inhibitors for the treatment of neurological disorders (update 2024).Exploration of drug science · 2025Article
- From compulsivity to compulsion: the neural basis of compulsive disorders.Nature reviews. Neuroscience · 2024Review
- Repurposing Niclosamide as a plausible neurotherapeutic in autism spectrum disorders, targeting mitochondrial dysfunction: a strong hypothesis.Metabolic brain disease · 2024Review
- DNA methylation clocks for clawed frogs reveal evolutionary conservation of epigenetic aging.GeroScience · 2024Article
- Persistent enhancement of basolateral amygdala-dorsomedial striatum synapses causes compulsive-like behaviors in mice.Nature communications · 2024Article
- Compulsive-like Behaviors in Amyloid-β 1-42-Induced Alzheimer's Disease in Mice Are Associated With Hippocampo-cortical Neural Circuit Dysfunction.Biological psychiatry global open science · 2023Article
- Training-induced circuit-specific excitatory synaptogenesis in mice is required for effort control.Nature communications · 2023Article
- Article
- Landscape and future directions of machine learning applications in closed-loop brain stimulation.NPJ digital medicine · 2023Review
- SAPAP3, SPRED2, and obsessive-compulsive disorder: the search for fundamental phenotypes.Frontiers in molecular neuroscience · 2023Article
- A closer look to neural pathways and psychopharmacology of obsessive compulsive disorder.Frontiers in behavioral neuroscience · 2023Review
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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