Abstract

Depression and anxiety disorders affect a great number of people worldwide. Whereas singular factors have been associated with the pathogenesis of psychiatric disorders, growing evidence emphasizes the significance of dysfunctional neural circuits and signaling pathways. Hence, a systems biology approach is required to get a better understanding of psychiatric phenotypes such as depression and anxiety. Furthermore, the availability of biomarkers for these disorders is critical for improved diagnosis and monitoring treatment response. In the present study, a mouse model presenting with robust high versus low anxiety phenotypes was subjected to thorough molecular biomarker and pathway discovery analyses. Reference animals were metabolically labeled with the stable (15)N isotope allowing an accurate comparison of protein expression levels between the high anxiety-related behavior versus low anxiety-related behavior mouse lines using quantitative mass spectrometry. Plasma metabolomic analyses identified a number of small molecule biomarkers characteristic for the anxiety phenotype with particular focus on myo-inositol and glutamate as well as the intermediates involved in the tricarboxylic acid cycle. In silico analyses suggested pathways and subnetworks as relevant for the anxiety phenotype. Our data demonstrate that the high anxiety-related behavior and low anxiety-related behavior mouse model is a valuable tool for anxiety disorder drug discovery efforts.

Highlights

  • For an improved understanding of the etiology of complex diseases such as psychiatric disorders the elucidation of mo

  • In order to analyze the proteomes of the HAB and LAB mouse lines in greater detail, we have used a comprehensive and accurate proteomics platform that involves metabolic labeling of live animals with stable isotopes followed by quantitative mass spectrometry (4 – 6)

  • Proteomic Analyses—For the sensitive quantitative proteomic analysis of the HAB/LAB mouse model we have used tissue specimens from NAB animals metabolically labeled with the stable isotope 15N as reference

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Summary

Introduction

For an improved understanding of the etiology of complex diseases such as psychiatric disorders the elucidation of mo-. We present results from our proteomic, metabolomic, and pathway analyses of HAB versus LAB mice and discuss their significance with regard to the anxiety phenotype. We present data for the in-depth quantitative proteomic analyses of hippocampal and plasma proteins from the trait anxiety mouse model.

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Conclusion
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