MedicalResearch.com Interview with:
Dr. Melanie Ullrich PhD
MedicalResearch.com: What is the background for this study?
Response: Shortly after the first description of SPRED proteins in 2001, their in vivo functions, especially that of SPRED2, were completely unexplored. Thus we generated a mouse model which lacks functional SPRED2 expression. In our previous study, we identified SPRED2 as a critical regulator of stress hormone release from the hypothalamic-pituitary-adrenal (HPA) axis. In SPRED2 KO mice levels of corticotropin-releasing hormone, adrenocorticotropic hormone, and corticosterone are elevated, a feature often associated with obsessive-compulsive disorders (OCD) in humans. In fact SPRED2 KO mice showed clear signs of OCD-like behavior demonstrated by excessive self-grooming up to the level of self-inflicted lesions. Treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine alleviated excessive grooming, confirming the OCD-like nature of the disease.
Therefore, the first main finding of our study is that mutations in the SPRED2 gene have to be considered as a possible risk factor for the development of OCD-like diseases.
MedicalResearch.com: What are the main findings?
Response: In order to detect the pathophysiological basis, we investigated synaptic transmission in two brain regions associated with the development of OCD: In striatum and amygdala. While a large body of studies clearly relates OCD symptoms to alterations in the activity of cortico-striato-thalamo-cortical (CSTC) circuits, a possible impact of the amygdala on the development of OCDs is suggested but only sparely investigated to date. Electrophysiological recordings detected an increased excitability at cortico-striatal synapses, but a rather distinct increase at thalamo-amygdala synapses in SPRED2 KOs, which was accompanied by altered neuron morphology in the lateral amygdala.
Thus, our second main discovery is that the amygdala plays a critical role in the pathogenesis of OCD.
SPRED proteins are inhibitors of Ras/ERK-MAPK signaling, a highly conserved pathway regulating gene transcription and cell proliferation. In SPRED2 KO mice, the Ras/ERK-MAPK cascade is over-activated, leading to a dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This is the molecular basis for excitability changes at thalamo-amygdala synapses and is caused upstream by a higher expression and activity of the brain-specific pathway activator, the receptor tyrosine kinase TrkB. Since downregulation of signaling activity using the MEK inhibitor selumetinib reduced OCD-like grooming in SPRED2 KO mice, we identified the TrkB/Ras/ERK-MAPK pathway as a novel mechanism involved in OCD pathology, which is our third main finding.
MedicalResearch.com: What should readers take away from your report?
Response: Upregulation of the proliferative Ras/ERK-MAPK pathway is currently a known trigger of cancer pathogenesis and developmental disorders like rasopathies. However, our study is initial in presenting a comprehensive mechanism how increased activity of this cascade can cause OCD-related behavior. We also provide clear evidence that, in addition to the known CSTC circuitry, limbic structures like amygdala contribute manifestly to the pathology of OCD. Furthermore, we identified SPRED2 not only as an essential factor in the pathogenesis of OCD, but also as a critical regulator of synaptic transmission in different brain regions and as a new regulator of BDNF/TrkB pathways.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: OCD is a multifactorial disease and pathogenesis is associated with mutations, e.g. in the serotonin transporter gene or in dopamine- or glutamate receptors. Further studies addressing the cause of OCD should consider SPRED2 as a potential risk factor and patients with unknown etiology should be screened for SPRED2 mutations. Diagnostic procedures, e.g. neuroimaging of disease-triggering brain structures in patients should involve the investigation of amygdala circuits in addition to the CTSC circuits.
Our research also offers new therapy options for OCD patients. To date, antidepressants like fluoxetine are used to treat OCD, however, their mechanism of action is unspecific and often not related to the cause of disease. In case of an up-regulated Ras/ERK-MAPK cascade as causative for OCD, drugs that inhibit this cascade are already available and some of them are approved for human treatment. However, they are actually anti-cancer drugs and a benefit with regard to undesired side effects is uncertain. Since SPRED2 KO mice are responsive to both SSRI treatment and Ras/ERK pathway inhibition by selumetinib, they are a valuable model for in vivo monitoring of further experimental treatments that might precede clinical studies with human patients.
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M Ullrich, M Weber, A M Post, S Popp, J Grein, M Zechner, H Guerrero González, A Kreis, A G Schmitt, N Üçeyler, K-P Lesch, K Schuh. OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency. Molecular Psychiatry, 2017; DOI: 10.1038/mp.2016.232
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