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.

NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice

“…The latter effect is in agreement with recent findings showing hyperactive ERK signalling to be a cause of obsessive compulsive disorder-like (i.e. self-grooming) behaviours in mice ( Ullrich et al , 2018 ). Nevertheless, since we tested self-grooming in a social context ( Silverman et al , 2010 ), we cannot exclude that the behaviour that we observed also has a social meaning and is not entirely obsessive/repetitive in nature.…”

Astrocytic Glutamate Transporter 1 (GLT1) Deficiency Reduces Anxiety- and Depression-Like Behaviors in Mice

“…*p < 0.05. less fear toward the stimulus, which was also reflected by less anxiety-like behaviors in the EPM of astrocytic GLT1 deficient mice. Notably, similar decrement of anxiety was also found in a SPRED2-deficient mouse model of obsessive compulsive disorder (OCD) (Ullrich et al, 2018). However, the reduced anxiety-like behaviors in OCD mice is controversial to traditional knowledge that anxiety or depression is commonly comorbid with OCD.…”

RAS Proteins and Their Regulators in Human Disease

“…In these mice, RAS.GTP and MAPK signaling were elevated, consistent with loss of neurofibromin function. The OCD phenotype could be reversed by antipsychotic drugs, or, remarkably, by MEK inhibitors (Ullrich et al, 2017). …”